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Treatment of attention deficit hyperactivity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation
Neuropsychiatric Disease and Treatment
... With an increasing rate of ADHD diagnosis worldwide, a sharp rise in the number of prescriptions of MPH to young children and adolescents has been recorded (Rabiner, 2013), despite an incomplete understanding of the drug's effects on the adolescent brain. Non-stimulant alternative treatments, such as the noradrenaline re-uptake inhibitor atomoxetine, are also often prescribed (Warrer et al., 2016), and more recently, administration of the aromatic amino acid, tyrosine, a precursor of dopamine and noradrenaline, has also been tested and shown to be effective (Hinz et al., 2011). Alternatively, the use of exercise as a non-drug treatment paradigm is also recently gaining increasing support, both alone and in combination with MPH (Choi et al., 2015). ...
... The MPH-induced increase of brain tyrosine levels may indeed be relevant to recent neuropsychological studies reporting that tyrosine-free amino acid mixtures disrupt performance in a range of behavioural and cognitive tasks that are dependent on dopamine and noradrenaline levels (Coull et al., 2012). Also of interest to this study is a recent clinical finding which demonstrates that administration of tyrosine-rich amino acid mixtures effectively diminish ADHD symptoms in some children (Hinz et al., 2011). Therefore, it is possible that MPH alleviates ADHD symptoms in two manners: (1) via blockage of DAT and NET, and (2) by enhancing the brain pool of tyrosine and phenylalanine as demonstrated here. ...
... Given that MPH increased cerebral levels of the precursors of catecholamine synthesis namely, phenylalanine and tyrosine, the findings of the present study further strengthen the catecholamine theory of ADHD. In line with this, a previous clinical study indeed found that the administration of tyrosine-rich amino acid mixtures effectively diminish ADHD symptoms in some affected children (Hinz et al., 2011). In addition to the catecholamine theory of ADHD, abnormalities of amino acid neurotransmission have also been suggested to be involved in ADHD. ...
The psychostimulant methylphenidate (MPH) is increasingly used in the treatment of attention deficit hyperactivity disorder (ADHD). While there is little evidence for common brain pathology in ADHD, some studies suggest a right hemisphere dysfunction among people diagnosed with the condition. However, in spite of the high usage of MPH in children and adolescents, its mechanism of action is poorly understood. Given that MPH blocks the neuronal transporters for dopamine and noradrenaline, most research into the effects of MPH on the brain has largely focused on these two monoamine neurotransmitter systems. Interestingly, recent studies have demonstrated metabolic changes in the brain of ADHD patients, but the impact of MPH on endogenous brain metabolites remains unclear. In this study, a proton nuclear magnetic resonance (¹H NMR)-based metabolomics approach was employed to investigate the effects of MPH on brain biomolecules. Adolescent male Sprague Dawley rats were injected intraperitoneally with MPH (5.0 mg/kg) or saline (1.0 ml/kg), and cerebral extracts from the left and right hemispheres were analysed. A total of 22 variables (representing 13 distinct metabolites) were significantly increased in the MPH-treated samples relative to the saline-treated controls. The upregulated metabolites included: amino acid neurotransmitters such as GABA, glutamate and aspartate; large neutral amino acids (LNAA), including the aromatic amino acids (AAA) tyrosine and phenylalanine, both of which are involved in the metabolism of dopamine and noradrenaline; and metabolites associated with energy and cell membrane dynamics, such as creatine and myo-inositol. No significant differences in metabolite concentrations were found between the left and right cerebral hemispheres. These findings provide new insights into the mechanisms of action of the anti-ADHD drug MPH.
... In the endogenous state, where no or insufficient serotonin or dopamine precursors are ingested, competitive inhibition does not exist. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] synthesis Aromatic-L-amino acid decarboxylase (AADC) metabolizes L-dopa to dopamine, 5-HTP to serotonin, histidine to histamine, and phenylalanine to phenylethylamine. Competitive inhibition may exist between the four precursors for metabolism by AADC. ...
... Administering L-dopa without balanced serotonin precursor concentrations may decrease AADC serotonin synthesis. This causes a L-dopa-induced serotonin precursor RND, Figure 2. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] Transport Organic Cation Transporters (OCT) transport the centrally acting monoamines (serotonin, dopamine, norepinephrine, and epinephrine) and their precursors bidirectionally across cell membranes. OCT transports precursors into the cellular structures where AADC metabolism occurs. ...
... Subsequent serotonin depletion represents a serotonin precursor RND. [5][6][7][8][9][10][11][49][50][51][52][53][54][55][56] ...
Hinz M, Stein A, Cole T, McDougall B, Westaway M. Neuropsychiatr Dis Treat. 2016;12:763–775.
The Editor-in-chief and Publisher of Neuropsychiatric Disease and Treatment wish to retract the published article.
Following the conclusion of our investigation the decision has been made to retract the published article. The authors did not provide the requested IRB and informed consent information relating to this study and it was determined the study did not meet the ethical publication requirements for research involving human subjects. These requirements are based on guidelines issued by the World Medical Association and the International Committee of Medical Journal Editors. Additionally, the authors did not provide the study protocols, raw data and other study documents relating to this study as requested. Given our concerns about the standard of research ethics, competing interests and that the authors have not supplied the information we requested to verify and validate the reported findings, the editor has determined the article should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... To understand the discussions contained herein, the concepts of the endogenous state and competitive inhibition state need to be defined. 1,[12][13][14][15][16][17][18][19][20] Humans taking no supplemental serotonin or dopamine amino acid precursors are in the endogenous state. The endogenous state also exists when L-dopa or 5 ...
... This limits the amount of dopamine and serotonin synthesized to levels less than are required to place the system into the competitive inhibition state. [12][13][14][15][16][17][18][19][20] When daily dopamine and dopamine amino acid requirements are higher than can be achieved in a normal or optimal diet, the state is known as a relative nutritional deficiency. 12 The concept of competitive inhibition between serotonin and dopamine is well known to science. ...
... To date, the only published methodology for optimization of the competitive inhibition state is Organic Cation Transporter Type 2 (OCT2) functional status determination. [12][13][14][15][16][17][18][19][20] The focus of this paper is not L-dopa efficacy, which has been firmly established by numerous past studies; this paper focuses on management of L-dopa dosing utilizing a novel technique that identifies overdose in the competitive inhibition state relative to optimal daily dosing, and assists in identifying the optimal dosing range. ...
Hinz M, Stein A, Cole T. Drug Healthc Patient Saf. 2014;6:93—99.
The Editor-in-chief and Publisher of Drug, Healthcare and Patient Safety wish to retract the published article.
Following the conclusion of our investigation the decision has been made to retract the published article. The authors did not provide the requested IRB and informed consent information relating to this study and it was determined the study did not meet the ethical publication requirements for research involving human subjects. These requirements are based on guidelines issued by the World Medical Association and the International Committee of Medical Journal Editors. Additionally, the authors did not provide the study protocols, raw data and other study documents relating to this study as requested. Given our concerns about the standard of research ethics, competing interests and that the authors have not supplied the information we requested to verify and validate the reported findings, the editor has determined the article should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... All of this is avoided with the amino acid administration approach guided by MTO, because ADHD responds well to this RND.4 A previous study indicated that pediatric ADHD management with amino acid administration guided by MTO which addressed the associated monoamine RND may be more effective than methylphenidate and atomoxetine.4 ...
... The optimal phase 3 ranges of serotonin and dopamine are achieved with the benefit of MTO. This is a complex task because, in the competitive inhibition state, changing one amino acid precursor changes all components of the equation shown in Figure 2.3,4,6,12 ...
... L-lysine prevents loose hair follicles in a bariatric medical practice. L-cysteine is administered to compensate for L-tyrosine-induced depletion of sulfur amino acids.3,4,6,12 ...
Two primary categories of nutritional deficiency exist. An absolute nutritional deficiency occurs when nutrient intake is not sufficient to meet the normal needs of the system, and a relative nutritional deficiency exists when nutrient intake and systemic levels of nutrients are normal, while a change occurs in the system that induces a nutrient intake requirement that cannot be supplied from diet alone. The purpose of this paper is to demonstrate that the primary component of chronic centrally acting monoamine (serotonin, dopamine, norepinephrine, and epinephrine) disease is a relative nutritional deficiency induced by postsynaptic neuron damage.
Monoamine transporter optimization results were investigated, reevaluated, and correlated with previous publications by the authors under the relative nutritional deficiency hypothesis. Most of those previous publications did not discuss the concept of a relative nutritional deficiency. It is the purpose of this paper to redefine the etiology expressed in these previous writings into the realm of relative nutritional deficiency, as demonstrated by monoamine transporter optimization. The novel and broad range of amino acid precursor dosing values required to address centrally acting monoamine relative nutritional deficiency properly is also discussed.
Four primary etiologies are described for postsynaptic neuron damage leading to a centrally acting monoamine relative nutritional deficiency, all of which require monoamine transporter optimization to define the proper amino acid dosing values of serotonin and dopamine precursors.
Humans suffering from chronic centrally acting monoamine-related disease are not suffering from a drug deficiency; they are suffering from a relative nutritional deficiency involving serotonin and dopamine amino acid precursors. Whenever low or inadequate levels of monoamine neurotransmitters exist, a relative nutritional deficiency is present. These precursors must be administered simultaneously under the guidance of monoamine transporter optimization in order to achieve optimal relative nutritional deficiency management. Improper administration of these precursors can exacerbate and/or facilitate new onset of centrally acting monoamine-related relative nutritional deficiencies.
... Therefore, chronic symptoms do not wax and wane as might be predicted by the laboratory results obtained in the endogenous state.5,8 Previous writings of the authors demonstrated relative nutritional deficiencies in Parkinson’s disease,5 chronic depression,9,12 Crohn’s disease,2 and attention deficit hyperactivity disorder without any findings that would support an AND.3 Restoration of regulatory function in these RND conditions is only possible when transporter-dependent monoamine concentrations are elevated above normal and properly balanced in the competitive inhibition state (see Figure 1).1–12 ...
... In chronic disease states the leading cause of electrical dysfunction is monoamine-related RND, secondary to damage to postsynaptic neuronal structures caused by neurotoxins, trauma, biologics, and/or genetic predisposition. The only way to compensate for damaged electrical flow is to properly balance serotonin and dopamine in the competitive inhibition state through administration of amino acid precursors under the guidance of OCT assay determination.2,3,5,7,8 ...
... Proper OCT assay requires that initially the serotonin and dopamine systems are placed in the competitive inhibition state simultaneously, while administering adequate amounts of serotonin and dopamine amino acid precursors. The assay results are then compared in order to determine the change in urinary serotonin and dopamine concentrations associated with changes in amino acid precursor dosing values.2,3,5,6,11 ...
... Double-blind, placebo-controlled studies reveal that in depression and ADHD treatment, the placebo response is greater than the drug effect in relief of symptoms. 7,8 This leads to the argument that discontinuation of a drug's clinical effects predominantly represents a placebo relapse rather than drug tachyphylaxis. 9,10 This paper presents the novel reuptake inhibitor monoamine depletion theory, which explains why symptoms that are controlled at the start of treatment return, irrespective of the cause of initial relief (placebo relapse or drug tachyphylaxis). ...
... These precursors cross the blood-brain barrier and are synthesized in the CNS into new monoamine molecules. 8,9,[11][12][13][14][15][16] ...
... A full discussion of the scientific basis for each of these amino acid and cofactor nutrients is covered in the authors' previous writings. 8,9,[11][12][13][14][15][16][20][21][22] A brief overview is as follows. L-tyrosine and 5-HTP are dopamine and serotonin precursors, respectively. ...
Hinz M, Stein A, Uncini T. Drug Healthc Patient Saf. 2011;3:69–77.
The Editor-in-chief and Publisher of Drug, Healthcare and Patient Safety wish to retract the published article.
Following the conclusion of our investigation the decision has been made to retract the published article. The authors did not provide the required IRB and informed consent information relating to this study and it was determined the study did not meet the standard ethical publication requirements for studies involving human subjects in research. These requirements are based on guidelines issued by the World Medical Association and the International Committee of Medical Journal Editors. Additionally, the authors did not provide the required study protocols, raw data and other study documents relating to this study as requested. Given our concerns about the standard of research ethics, competing interests and that the authors have not supplied the information we requested to verify and validate the reported findings, the editor has determined the article should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... The marketing model is promoted primarily for disease states that have a high positive placebo effect. In many studies, attention deficit hyperactivity disorder and depression are associated with a positive placebo effect of 40%–50%.5,9 Almost half of the patients with these diseases improve significantly in 1 month while being treated with placebo. ...
... This occurs when a subject is taking no amino acids. The “ competitive inhibition state” is found when significant amounts of both serotonin and dopamine amino acid precursors are being taken simultaneously.6,9–11,13 This clinical review is undertaken exclusively to discuss the testing performed in the endogenous state with spot baseline urine samples. ...
... Indeed, physicians have said under questioning, “I like this approach; at least half of my patients get better in the first month”. This approach completely ignores the placebo effect while quietly exploiting it in the background for the marketing of urinary monoamine assays.5,9 ...
... Functions dependent on only serotonin or dopamine concentrations in the endogenous state can be impacted in a predictable manner by changes in levels of either in the balanced competitive inhibition state which is the foundation of APRESS.4,5,8,10,11 APRESS physiology is not intuitive. ...
... Three primary functions affect intracellular and extracellular serotonin and catecholamine levels: synthesis, metabolism, and transport.3–5,7,8,10–12 These functions occur in either the endogenous or competitive inhibition state.3–8 ...
... L-tyrosine or L-dopa depletes serotonin when dominant.4,5,8,10,11 ...
... Moreover, the selective serotonin reuptake inhibitor (SSRI) fluoxetine has been shown to be effective in reducing ADHD-related symptoms in children (Barrickman et al. 1991;Quintana et al. 2007) and to improve the efficacy of stimulants in human and animal studies (Gammon & Brown, 1993;Findling, 1996;Gainetdinov et al. 1999). Further, the concurrent administration of 5-HT and dopamine amino-acid precursors can improve ADHD symptoms (Hinz et al. 2011). However, replication is needed as these studies are limited by comorbid samples (Quintana et al. 2007) and nonrandomized trials in small samples (Barrickman et al. 1991). ...
... However, 5-HT modulates specifically ADHD-relevant impulsivity-related functions mediated by ventrolateral-prefrontal regions which are dependent on 5-HT input such as inhibitory control and reward-related decisionmaking (Dalley & Roiser, 2012). The up-regulation with a 5-HT agonist of key right-hemispheric IFC-striatal activation that is typically abnormal in ADHD suggests that abnormal 5-HT may be underlying abnormal activation in these networks and not just catecholamine systems, in line with accumulating evidence of a role of 5-HT in ADHD (Barrickman et al. 1991;Spivak et al. 1999;Quintana et al. 2007;Oades, 2008;Gizer et al. 2009;McGough et al. 2009;Rommelse et al. 2010;Zepf et al. 2010;Hinz et al. 2011). However, it cannot be ruled out that fluoxetine had no indirect effects on other neurotransmitter systems which are known to be influenced by 5-HT such as dopamine, acetylcholine and other monoamines (Mongeau et al. 1997;Bymaster et al. 2002;Oades, 2008). ...
Background:
Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD.
Method:
Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects.
Results:
Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo.
Conclusions:
The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.
... When competitive inhibition under this system exists, changes to either serotonin or dopamine concentrations individually will affect both serotonin and dopamine concentrations in a predictable manner. 1,[7][8][9][10][11][12][13][14][15][16] Relative nutritional deficiency A relative nutritional deficiency (RND) exists when optimal nutrient intake cannot meet system needs. Parkinson's disease may induce many RNDs associated with depletions of serotonin, dopamine, norepinephrine, epinephrine, thiols (homocysteine, l-methionine, S-adenosyl-l-methionine, S-adenosyl-homocysteine, cystathione, l-cysteine, and glutathione), l-tyrosine, and l-tryptophan. ...
... If dopamine depletion is induced, 5-HTP is no longer functioning as a nutrient; it is a drug. 1,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] When l-dopa is administered as a single agent, it may deplete serotonin, and would then be considered a drug, not a nutrient. 1,7,[30][31][32][33][34] ...
Hinz M, Stein A, Cole T. Clin Pharmacol. 2014;6:189–194.
The Editor-in-chief and Publisher of Clinical Pharmacology: Advances and Applications wish to retract the published article.
This perspective article cites several original research articles published by the authors, which have recently been retracted. This article draws on the findings from those original research articles to form central arguments and discussion, and as a result of the research articles’ retraction, the argument presented in this article is no longer valid and the editor has determined it should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... When it is administered as a single agent, dopamine depletion may occur. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] If it induces dopamine depletion, then 5-HTP no longer functions as a nutrient; it is a drug. L-dopa may be administered as a nutrient. ...
... When it is administered as a single agent, serotonin depletion may occur. [10][11][12][13][14][15][16][17][18][22][23][24][25][26][27][28][29] If it induces serotonin depletion, then L-dopa no longer functions as a nutrient; it is a drug. ...
Hinz M, Stein A, Cole T. Clin Pharmacol. 2014;6:161–169.
The Editor-in-chief and Publisher of Clinical Pharmacology: Advances and Applications wish to retract the published article.
This perspective article cites several original research articles published by the authors, which have recently been retracted. This article draws on the findings from those original research articles to form central arguments and discussion, and as a result of the research articles’ retraction, the argument presented in this article is no longer valid and the editor has determined it should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... 8 Lysine is important for lowering cholesterol levels, absorption of calcium and formation of collagen, etc. whereas, methionine can dissolve fats and prevent liver damage due to acetaminophen (Tylenol) poisoning, and tryptophan plays a very important role in the improvement of normal growth in infants and adults also finds its usage in treating many diseases and disorders including arguably its utilities in one of the most challenging fields in modern times ADHD (Attention deficit hyperactive disorder). [9][10][11][12][13] Although there have been reports on the nutritional makeup of several bamboo species from throughout the world, their values differ among the species, products, and locality due to many significant reasons. 2,5,8 Notable works on crude protein, fiber, fat, carbohydrates, vitamins, and minerals for the fresh tender shoots of many bamboo species were also carried out. ...
Bamboo is a versatile grass with multiple applications and yielding edible tender shoots. Juvenile shoots are a delicacy for many ethnic communities all over the globe and are rich in essential nutrients for human health. A study was conducted to identify the concentrations of essential amino acids viz. Lysine, Methionine, and Tryptophan with Crude protein, Crude fiber, and Carbohydrates in both fresh and processed tender shoots of seven commercial bamboo species available in Arunachal Pradesh, India. Concentrations of all nutritional parameters considered for this study are comparable with conventional foods and some values were higher in processed bamboo shoot products than those of fresh tender shoots. Findings of this study revealed that bamboo shoots and their processed products are highly nutritious which can provide opportunities in both nutritional as well as economic aspects to the people of the country in general and the state in particular. It may provide opportunities to combat poverty and hunger by opting for new readily available food sources and may also provide scope to overcome malnutrition, especially in the areas where it is widely prevalent.
... L-tyrosine is metabolized to L-dopa, which in turn is metabolized by AADC to dopamine. [2][3][4][5][6][7][8] Competitive inhibition between serotonin and dopamine exists in transport, synthesis, and metabolism when precursors of both are administered simultaneously in levels that are high enough and properly balanced. 5,6 Objective verification of the competitive inhibition state is under the apical regulatory super system (APRESS) model. ...
Hinz M, Stein A, Cole T. Neuropsychiatr Dis Treat. 2014;10:2331–2337.
The Editor-in-chief and Publisher of Neuropsychiatric Disease and Treatment wish to retract the published article.
This perspective article cites several original research articles published by the authors, which have recently been retracted. This article draws on the findings from those original research articles to form central arguments and discussion, and as a result of the research articles’ retraction, the argument presented in this article is no longer valid and the editor has determined it should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... Administration of supplemental L-tyrosine with phenelzine writing no concerns have been raised regarding concomitant administration of L-tyrosine with phenelzine. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] The primary cause of phenelzineassociated hypertensive crisis ...
Hinz M, Stein A, Cole T, Ryan P. Clin Pharmacol. 2014;6:107–110.
The Editor-in-chief and Publisher of Clinical Pharmacology: Advances and Applications wish to retract the published article.
This review article cites several original research articles published by the authors, which have recently been retracted. This article draws on the findings from those original research articles to form central arguments and discussion, and as a result of the research articles’ retraction, the argument presented in this article is no longer valid and the editor has determined it should be retracted.
Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.
The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.
... There is also evidence that response to stimulants is mediated by 5-HT in animal (Gainetdinov et al. 1999) and human studies as an association between serotonergic genes and Methylphenidate response has been observed (McGough et al. 2009;Banerjee et al. 2012). In addition, the co-administration of 5-HT and dopamine amino acids precursors in children with ADHD has been shown to lead to a significant improvement in symptoms (Hinz et al. 2011). Therefore, when used in combination, Fluoxetine may lead to better regulation of the increased dopamine induced by Methylphenidate, leading to clinical improvement (Barrickman et al. 1991;Gammon and Brown 1993;Findling 1996;Quintana et al. 2007). ...
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share brain function abnormalities during cognitive flexibility. Serotonin is involved in both disorders, and selective serotonin reuptake inhibitors (SSRIs) can modulate cognitive flexibility and improve behavior in both disorders. Thus, this study investigates shared and disorder-specific brain dysfunctions in these 2 disorders during reward reversal, and the acute effects of an SSRI on these. Age-matched boys with ADHD (15), ASD (18), and controls (21) were compared with functional magnetic resonance imaging (fMRI) during a reversal task. Patients were scanned twice, under either an acute dose of Fluoxetine or placebo in a double-blind, placebo-controlled randomized design. Repeated-measures analyses within patients assessed drug effects. Patients under each drug condition were compared with controls to assess normalization effects. fMRI data showed that, under placebo, ASD boys underactivated medial prefrontal cortex (mPFC), compared with control and ADHD boys. Both patient groups shared decreased precuneus activation. Under Fluoxetine, mPFC activation was up-regulated and normalized in ASD boys relative to controls, but down-regulated in ADHD boys relative to placebo, which was concomitant with worse task performance in ADHD. Fluoxetine therefore has inverse effects on mPFC activation in ASD and ADHD during reversal learning, suggesting dissociated underlying serotonin abnormalities.
... There were three papers in Neuropsychiatric Disease and Treatment that attracted the most attention in the last year, all recording more than 10,000 hits since publication. Varying widely in subject matter, by far the most popular of the trio, with almost 30,000 hits, was a publication on a new physical method for treating psychiatric disorders, in this case bipolar disorder, 1 while publications on alcohol consumption and cognitive risk 2 and dietary treatment of attention deficit hyperactivity disorder (ADHD) 3 were in second and third place, respectively. ...
More than 65% of the elderly population globally suffers from dementia. The term “smart drug” refers to any drug substance that positively impacts mental skills. Nootropics are agents that are used for boosting the performance of the brain and to increase one's concentration. These are also called cognitive enhancers as these can enhance memory, creativity, awareness, and attention. Natural sources, as well as synthetic approaches, both, are being employed by researchers worldwide for developing smart drugs. Smart drugs are intended to enhance academic, social, as well as career performance. These drugs work by boosting the oxygen supply and nutrition to the brain and are useful for treating various neurodegenerative disorders. Several mechanistic pharmacological approaches have been explored for the development of smart drugs and enhancement of brain activity, the most prominent ones being glutamatergic, dopaminergic, serotonergic, and cholinergic pathways. This chapter reviews the various approaches for developing synthetic smart drugs and their applications and limitations.
The onset of Attention-Deficit-Hyperactivity-Disorder (ADHD) in childhood is characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. A chronic deficit of serotonin (5-HT) at the synapse may trigger symptoms of ADHD. This review focuses on neuro-anatomical, experimental and clinical pharmacological evidence, as well as the genetic underpinnings of serotoninergic involvement in the etiology of ADHD. Neuro-anatomical investigations suggest that serotonin through the orbitofrontal-striatal circuitry may regulate behavioral domains of hyperactivity and impulsivity in ADHD. Studies from animal models of ADHD indicate intimate interplay between 5-HT and dopaminergic neurotransmission. Selective serotonin re-uptake inhibitors, as also non-stimulant drugs acting on the 5-HT system are, however, clinically effective. They impart less severe side effects in patients with no risk of addiction. Oral administration of L-tryptophan, the amino acid precursor of 5-HT, significantly alleviates ADHD symptoms. Given the multifactorial nature of ADHD, candidate gene and genome-wide association studies have suggested that serotoninergic gene variants are associated with increased risk of ADHD with each locus individually exerting a modest effect on overall risk.
Copyright © 2015. Published by Elsevier Ltd.
This 10-week study assessed the efficacy of atomoxetine in combination with psychoeducation compared to placebo and psychoeducation in the improvement of Quality of Life in Swedish stimulant-naive children and adolescents with attention deficit/hyperactivity disorder. A total of 99 patients were treated with atomoxetine (49 patients) or placebo (50 patients) for 10 weeks and assessed regarding broader areas of functioning using the Quality of Life measures Child Health and Illness Profile-Child Edition (CHIP-CE), Family Strain Index [FSI; equivalent to the Family Burden of Illness Module used in the study], Appraisal of Stress in Child-Rearing (ASCR), Five to fifteen (FTF), "I think I am" ("Jag tycker jag är"), and Children's Depression Rating Scale-Revised (CDRS-R) before and after the active treatment phase. Simultaneously, the patients' parents participated in a 4-session psychoeducation program. A statistically significant difference in favor of atomoxetine was seen in the improvement from baseline to study endpoint for the CHIP-CE domains "Achievement" and "Risk avoidance", for the FSI total score, for the ASCR section (I) domain "Child as a burden", for all FTF domains except for "Language and Speech", and for the CDRS-R total score. No difference between treatment groups was observed in the patient-assessed evaluation of self-esteem using the "I think I am" scale. Atomoxetine combined with psychoeducation had a positive effect on various everyday coping abilities of the patients as well as their families during 10 weeks of treatment, whereas the patients' self-image and the parents' image of the climate in the family were not significantly improved.
To compare the efficacy, safety, and tolerability of once-daily administration of modified-release methylphenidate (MPH MR) with placebo in children with attention-deficit/hyperactivity disorder (ADHD).
The study was a 3-week, double-blind, 32-site, randomized clinical trial comparing MPH MR with placebo. Children were 6 to 16 years of age, had a diagnosis of ADHD, and had not failed a previous trial of stimulant treatment for ADHD. After a 1-week, single-blind, placebo-washout period, participants received a once-daily dose of MPH MR or placebo, which was started with 1 capsule (20 mg) and individually titrated up to a maximum of 3 capsules (60 mg). The primary outcome measure was specified as a reduction in ADHD symptom severity from the teacher version of the 10-item Conners' Global Index. Investigators, teachers, and parents evaluated safety.
The study randomized 321 children: 158 to MPH MR and 163 to placebo. Children in the MPH MR group were started on a dose of 20 mg/d and reached a mean dose of 40.7 mg/d (1.28 mg/kg/d) at endpoint. Compared with placebo, MPH MR significantly reduced ADHD symptoms ratings on the teacher version of the 10-item Conners' Global Index, on the parent version of the Conners' Global Index, on the parent assessment of global efficacy, and on investigator assessment of global improvement. The most common adverse events in the MPH MR group were headache, anorexia, abdominal pain, and insomnia. Only anorexia occurred at a rate that was significantly greater than placebo.
MPH MR administered once daily in the morning is effective and safe in controlling ADHD symptoms throughout the school day.
The authors assessed the efficacy of once-daily atomoxetine administration in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD).
In a double-blind study, children and adolescents with ADHD (N=171, age range=6-16 years) were randomly assigned to receive 6 weeks of treatment with either atomoxetine (administered once daily) or placebo.
Outcomes among atomoxetine-treated patients were superior to those of the placebo treatment group as assessed by investigator, parent, and teacher ratings. The treatment effect size (0.71) was similar to those observed in previous atomoxetine studies that used twice-daily dosing. Parent diary ratings suggested that drug-specific effects were sustained late in the day. Discontinuations due to adverse events were low (less than 3%) for both treatment groups, and no serious safety concerns were observed.
Once-daily administration of atomoxetine is an effective treatment for children and adolescents with ADHD.
Selective serotonin reuptake inhibitors (SSRIs) have been suspected of increasing the risk of bleeding. We examined the risk of upper gastrointestinal tract (GI) bleeding with use of antidepressant medication.
All users of antidepressants in the county of North Jutland, Denmark, from January 1, 1991, to December 31, 1995, were identified in the Pharmaco-Epidemiologic Prescription Database of North Jutland. In the Hospital Discharge Register, hospitalizations for upper GI bleeding were searched among the 26 005 users of antidepressant medications and compared with the number of hospitalizations in the population of North Jutland who did not receive prescriptions for antidepressants.
During periods of SSRI use without use of other drugs associated with upper GI bleeding, we observed 55 upper GI bleeding episodes, which was 3.6 times more than expected (95% confidence interval, 2.7-4.7), corresponding to a rate difference of 3.1 per 1000 treatment years. Combined use of an SSRI and nonsteroidal anti-inflammatory drugs or low-dose aspirin increased the risk to 12.2 (95% confidence interval, 7.1-19.5) and 5.2 (95% confidence interval, 3.2-8.0), respectively. Non-SSRIs increased the risk of upper GI bleeding to 2.3 (95% confidence interval, 1.5-3.4), while antidepressants without action on the serotonin receptor had no significant effect on the risk of upper GI bleeding. The risk with SSRI use returned to unity after termination of SSRI use, while the risks were similarly increased during periods of use and nonuse of non-SSRIs.
Selective serotonin reuptake inhibitors increase the risk of upper GI bleeding, and this effect is potentiated by concurrent use of nonsteroidal anti-inflammatory drugs or low-dose aspirin, whereas an increased risk of upper GI bleeding could not be attributed to other types of antidepressants.
OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype.
Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n = 47), ages 5 to 16 years, underwent a placebo-controlled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly.
Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36- or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher doses, parent report of side effects was not related to dose. In addition, younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose, there were no dose effects on blood pressure.
In children with ADHD-CT, the most common subtype of ADHD, increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms. In children with ADHD-PI, symptom improvement occurred at lower doses and less benefit was derived from higher doses. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite.
Pharmacotherapy with amphetamine is effective in the management of attention-deficit/hyperactivity disorder (ADHD), now recognized in adults as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine in children as well as adults.
The objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) among adults by using drug-placebo response curve methods.
We analyzed data from two double-blind, placebo-controlled, parallel design studies of adult patients (Study I, N = 280; Study II, N = 256) with DSM-IV-defined ADHD who were recruited by referral and advertising. Subjects were randomized to 10 weeks of treatment with atomoxetine or placebo, and were assessed with the Conners Adult ADHD Rating Scales and the Clinical Global Impression of ADHD Severity scale before and after treatment.
Those treated with atomoxetine were more likely to show a reduction in ADHD symptoms than those receiving placebo. Across all measures, the likelihood that an atomoxetine-treated subject improved to a greater extent than a placebo-treated subject was approximately 0.60. Furthermore, atomoxetine prevented worsening of most symptom classes.
From these findings, we conclude that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria.
Despite the persistence of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known about the efficacy and tolerability of stimulant medications in this age group.
To report the results of a multisite controlled study among adolescents with ADHD evaluating the efficacy and tolerability of osmotic-release oral system (OROS) methylphenidate.
Adolescents (N = 220) having a confirmed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of ADHD underwent dose titration to identify dosages of OROS methylphenidate that improved symptoms to predefined criteria. Subjects successfully completing the dose titration phase (n = 177) (ie, tolerated and responded to treatment and adhered to the protocol) were randomized to receive 2 weeks' treatment with their individualized dosage of OROS methylphenidate (18, 36, 54, or 72 mg once daily) or placebo. Treatment effectiveness was measured using investigator, parent, and adolescent assessments of ADHD.
A significant reduction from baseline in the investigator-rated ADHD Rating Scale, the primary efficacy measure, was found with OROS methylphenidate treatment compared with placebo. Similar findings were noted with parent- and adolescent-report measures. Based on a Clinical Global Impression improvement subscale score of much or very much improved, 52% of subjects in the OROS methylphenidate group improved compared with 31% receiving placebo. Thirty-seven percent of subjects required the maximum dosage of 72 mg/d. The incidence of drug-related adverse events was similar between the 2 study groups.
In adolescents, once-daily OROS methylphenidate significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/d.
Objective: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain information on the long-term neurological consequences of this therapy. Method: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed individuals. Results: In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows significant decreases in striatal dopamine and transporter density after oral administration of “therapeutic” doses in primates. Another shows morphological evidence of “trophic” dendritic growth in the brains of adult and juvenile rats given systemic injections mimicking “therapeutic” treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment. Conclusion: Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed. (J. of Att. Dis. 2007; 11(1) 8-16)
Millions of children in North America are diagnosed with attention deficit/hyperactivity disorder and treated with psychostimulants such as methylphenidate, dextroamphetamine, and methamphetamine. These drugs produce a continuum of central nervous system toxicity that begins with increased energy, hyperalertness, and overfocusing on rote activities. It progresses toward obsessive/compulsive or perseverative activities, insomnia, agitation, hypomania, mania, and sometimes seizures. They also commonly result in apathy, social withdrawal, emotional depression, and docility. Psychostimulants also cause physical withdrawal, including rebound and dependence. They inhibit growth, and produce various cerebral dysfunctions, some of which can become irreversible.
The “therapeutic” effects of stimulants are a direct expression of their toxicity. Animal and human research indicates that these drugs often suppress spontaneous and social behaviors while promoting obsessive/compulsive behaviors. These adverse drug effects make the psychostimulants seemingly useful for controlling the behavior of children, especially in highly structured environments that do not attend to their genuine needs.
Aims In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs.
Methods We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression.
Results We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10.8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0.8 (0.3,2.3). The estimate for ‘other antidepressants’ was 0.7 (0.3,1.6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid).
Conclusions Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.
Selective serotonin reuptake inhibitors (SSRIs) have been associated with serotonin depletion in platelets, potentially leading to abnormal aggregation and prolonged bleeding time. In view of the importance of serotonin in coronary thrombosis, and decreased platelet serotonin concentrations associated with SSRIs, the present study was performed to test the hypothesis of a decreased risk of acute myocardial infarction (AMI) associated with SSRIs.
We conducted a population-based case-control analysis using the UK General Practice Research Database (GPRD). A total of 3319 patients aged 75 years or younger free of clinical conditions predisposing to ischaemic heart disease, with a first-time diagnosis of AMI between 1992 and 1997, and 13 139 controls without AMI matched to cases for age, sex, general practice attended, and calendar time were included. Conditional logistic regression was used to estimate relative risks.
Adjusted odds ratios (with 95% CI) for current use of SSRIs, non-SSRIs, or other antidepressants, compared to the group of nonusers of antidepressants were 0.9 (95% CI 0.5,1.8), 0.9 (95% CI 0.7,1.2), and 1.3 (95% CI 0.6,2.8), respectively. As compared with nonuse of SSRIs, current use (regardless of any other antidepressants used) resulted in an adjusted OR of 1.1 (95% CI 0.7,1.6).
The current analysis provides evidence that SSRI exposure does not substantially decrease the risk of developing first-time AMI in patients free of factors predisposing to ischaemic heart disease. However, due to relatively small numbers of exposed subjects and the resulting wide confidence intervals, further studies may be needed to document a lack of effect of SSRIs in subjects without pre-existing diseases predisposing to AMI.
The effects of repeated fluoxetine (Flx) administration (5, 10, or 15 mg/kg i.p., twice daily for 21 days) on serotonin and 5-HIAA metabolism were examined in the hypothalamus, hippocampus, pons medulla and cerebral cortex of rats killed 1-28 days after the last dose. Dose-dependent weight loss was observed during treatment, followed by gradual and complete recovery of body weight over the following two weeks. Chronic Flx treatment caused a dose-dependent decrease in brain 5-HT levels (by between 10 and 50% depending on the region examined), lasting for 3-7 days after cessation of treatment with the lowest and intermediate doses, and for 7-14 days after cessation of the highest dose. 5-HIAA levels decreased more markedly (-20; -60% depending on the region examined) than those of 5-HT, and tended to overshoot during the recovery period. The prolonged reduction in brain 5-HT levels after chronic Flx treatment was similar to that seen in rats given very high doses of dexfenfluramine (d-fen), a drug which both blocks 5-HT uptake and increases its release. These data suggest that brain 5-HT and 5-HIAA depletion may reflect similar dose-related expressions of the drug's mechanisms of action.
This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and the therapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletion studies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved in antidepressant action, but the specific impairment that underlies depression is unclear and is likely to vary among patients. Results from neurotransmitter depletion studies in depressed patients who have responded to treatment suggest that, while interactions between NE and 5-HT are likely, neither of these 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressant drugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability of NE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent on the availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic and serotonergic systems-such as mirtazapine-may be dependent on the availability of both neurotransmitters for their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjects or worsened depression in unmedicated symptomatic patients with major depression. This finding suggests that the cause of depression is more complex than just an alteration in the levels of 5-HT and/or NE. For some patients, depression may be more directly caused by dysfunction in brain areas or neuronal systems modulated by monoamine systems. We propose that antidepressant drugs may enhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependent but as yet undiscovered process, restore function to brain areas modulated by monoamine neurons. Future research should focus on understanding the adaptive changes that follow enhancement of synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus. Research investigating the neurobiology of depression may be more informed if the focus is shifted to investigating areas of the brain modulated by monoamine systems rather than the monoamine systems themselves.
In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs.
We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression.
We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10. 8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0. 8 (0.3,2.3). The estimate for 'other antidepressants' was 0.7 (0.3,1. 6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid).
Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.
The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect.
Over the last 15 years, a number of transporters that translocate organic cations were characterized functionally and also identified on the molecular level. Organic cations include endogenous compounds such as monoamine neurotransmitters, choline, and coenzymes, but also numerous drugs and xenobiotics. Some of the cloned organic cation transporters accept one main substrate or structurally similar compounds (oligospecific transporters), while others translocate a variety of structurally diverse organic cations (polyspecific transporters). This review provides a survey of cloned organic cation transporters and tentative models that illustrate how different types of organic cation transporters, expressed at specific subcellular sites in hepatocytes and renal proximal tubular cells, are assembled into an integrated functional framework. We briefly describe oligospecific Na(+)- and Cl(-)-dependent monoamine neurotransmitter transporters ( SLC6-family), high-affinity choline transporters ( SLC5-family), and high-affinity thiamine transporters ( SLC19-family), as well as polyspecific transporters that translocate some organic cations next to their preferred, noncationic substrates. The polyspecific cation transporters of the SLC22 family including the subtypes OCT1-3 and OCTN1-2 are presented in detail, covering the current knowledge about distribution, substrate specificity, and recent data on their electrical properties and regulation. Moreover, we discuss artificial and spontaneous mutations of transporters of the SLC22 family that provide novel insight as to the function of specific protein domains. Finally, we discuss the clinical potential of the increasing knowledge about polymorphisms and mutations in polyspecific organic cation transporters.
Attention-deficit/hyperactivity disorder (ADHD) is typically treated over extended periods; however, few placebo-controlled, long-term studies of efficacy have been reported.
In a global multicenter study, children and adolescents who responded to an initial 12-week, open-label period of treatment with atomoxetine, a nonstimulant treatment for ADHD, were randomized to continued atomoxetine treatment or placebo for 9 months under double-blind conditions.
A total of 416 patients completed acute atomoxetine treatment and were randomized. At end point, atomoxetine was superior to placebo in preventing relapse defined as a return to 90% of baseline symptom severity (proportion relapsing: atomoxetine 65 of 292 [22.3%], placebo 47 of 124 [37.9%], p =.002). The proportion of patients with a 50% worsening in symptoms post-randomization was also lower on atomoxetine (atomoxetine 83 of 292 [28.4%], placebo 59 of 124 [47.6%], p <.001). Compared with patients in the placebo group, atomoxetine-treated patients had superior psychosocial functioning at end point. Discontinuations for adverse events were low in both groups, and tolerability was similar to that observed in acute treatment trials.
In patients who responded favorably to 12 weeks of initial treatment, atomoxetine was superior to placebo in maintaining response for the ensuing 9 months. This result supports the value of maintenance treatment with atomoxetine in patients with ADHD who respond to initial treatment.
FDA approved prescribing information for neutral sulfate salts of dextroamphetamine and amphetamine. Available from: http:// pi.shirecontent.com/PI/PDFs/AdderallXR_USA_ENG
- Shire
- Inc
Shire US Inc. FDA approved prescribing information for neutral sulfate salts of dextroamphetamine and amphetamine. Available from: http:// pi.shirecontent.com/PI/PDFs/AdderallXR_USA_ENG.PDF. Accessed Oct 14 2010.
FDA approved prescribing information for lisdexamfetamine dimesylate Available from: http://www. adhdinfocentre.com/vyvanse/Vyvanse%20Prescribing%20Information
- Adhd Centre
ADHD & ADD Information Centre. FDA approved prescribing information for lisdexamfetamine dimesylate. Available from: http://www. adhdinfocentre.com/vyvanse/Vyvanse%20Prescribing%20Information. PDF. Accessed Oct 14 2010.
Food and Nutrients in Disease Management
- M Hinz
FDA approved prescribing information for atomoxetine Available from: http://pi.lilly.com/us/strattera-pi.pdf
- Lilly
Lilly. FDA approved prescribing information for atomoxetine. Available
from: http://pi.lilly.com/us/strattera-pi.pdf. Accessed Oct 14 2010.
FDA approved prescribing information for dexmethylphenidate Available from
- Novartis
Novartis. FDA approved prescribing information for dexmethylphenidate.
Available from: http://www.pharma.us.novartis.com/product/pi/pdf/
focalin.pdf. Accessed Oct 14 2010.
In: Kohlstadt I, editor. Food and Nutrients in Disease Management
- M Hinz
- Depression
Hinz M. Depression. In: Kohlstadt I, editor. Food and Nutrients in
Disease Management. Boca Raton, FL: CRC Press; 2009.