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Physician’s Resource The physician’s psychoactive medication resource guide 25% of your patients taking an antidepressant will have weight gain and the weight gain is directly caused by the antidepressant.
Antidepressant Induced Weight Gain New Medical Breakthrough solves the antidepressant weight gain problem which affects 25% of your patients. The 4 clinical studies also show; liver enzymes, cholesterol, glucose and triglyceride levels back to normal in 6-weeks. Plus, with an average weight loss of 24-pounds in the 6 week trials, your patients finally have a solution for the weight gain. Click here to read what your patients can do to start losing the weight and begin feeling better quickly.
New information has just been released of the actual cause of antidepressant weight gain. The end  has finally come for Celexa weight gain, Effexor Weight gain, Cymbalta weight gain, Lexapro weight  gain, Paxil weight gain, Prozac weight gain and Zoloft weight gain. If you are taking an  antidepressant, other than an SSRS, you are in luck as well.  Clinical studies have now revealed the exact cause of antidepressant weight gain. And clinical  studies now confirm weight loss can happen when you do specific things. Click here to read more. Antidepressants and anti-psychotics were created to alter an area of the brain called the  Hypothalamus Pituitary-Adrenal Axis (HPA). The HPA is a system of hormones and glands. The  hormones within the HPA regulate serotonin. These medications are designed to increase the output of a hormone that is believed to lower  stress, depression and symptoms associated with mental disorders. This HPA system has a group of steroid hormones called Glucocorticoids, which regulate  carbohydrate, protein, and fat metabolism.  This HPA system needs to be in balance for the body to function properly.  The human brain will usually make up 2% of our overall body mass. However, our brain will use up  50% of glucose in the body. The brain depends on our glucose for energy.  Activity within this system generates messages of “energy on demand” and “energy on request.”  The activation of the adrenal system inhibits glucose uptake by tissue by inhibiting insulin release.  This process produces insulin resistance but increases hepatic glucose production. With inadequate “energy on request,” a condition called neuroglycopenia (a shortage of glucose in  the brain, also hypoglycemia.)  Symptoms associated with this condition: •Abnormal mentation (mental activity), thinking, impaired judgment  •Anxiety, moodiness, depression, crying, fear of dying  •Negativism, irritability, belligerence, combativeness, rage •Personality change, emotional lability (Very rapid fluctuations in intensity of emotions.)  •Fatigue, weakness, apathy, lethargy, daydreaming, sleep  •Confusion, amnesia, dizziness, delirium •Staring, "glassy" look, blurred vision, double vision  •Difficulty speaking, slurred speech •Ataxia (Loss of the ability to coordinate muscular movement.), incorordination,   sometimes mistaken for "drunkenness" •General motor deficit, paralysis, hemiparesis (Muscle weakness on one side of the body.) •Paresthesia (A skin sensation, such as burning, prickling, itching, or tingling, with no apparent physical cause.), headache  •Stupor, coma, abnormal breathing A decrease in brain glucose will activate other portions of the brain that release proteins, which stimulate food intake. When this happens, an increase in body weight is inevitable at this point. The increase in fat mass will generate a feedback signal to other hormones and insulin. These phenomena can also take place with prolonged stress, starvation, and continued heavy exercise, drugs or by certain chemicals. This results in the permanent activation of the feedback signal, which results in continued insulin resistance, hypertension and metabolic syndrome.          This is why individuals that are predisposed to diabetes are 2 to 3 times more likely to become
diabetic if they use an antidepressant or anti-psychotic medication. Another key hormone regulating weight that is also altered by glucocorticoid is leptin. There are two types of leptin, brain leptin and plasma leptin. Glucocorticoids increase both appetite as well as brain leptin secretion. Plasma leptin will store unwanted fats. The brain is the controlling factor in this system. The brain knows it needs an ample supply of glucose to survive. With this balanced system being altered with drug induced over stimulation of glucocorticoid, the brain sends a signal to increase plasma leptin for fat and glucose storage. This insures the brain of the needed glucose for survival. This increased plasma leptin works for the brain effectively in the short-term but ultimately leads to the destruction of the body. Obesity, diabetes, and a hormone – gland system that becomes too fatigued to function, is the final outcome. The human brain is remarkable and highly complex. But when it is threatened with survival, the automatic reaction is self-destructive. References: · "These studies suggest that the fat-cell derived hormone Leptin might play an important role. Leptin signals to the brain the size of the adipose tissue and is probably the most important peripheral signal for the long-term regulation of weight." Neurol Psychiatry · "Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant- like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders." January 31, 2006 the Department of Pharmacology, University of Texas Health Science Center · Massachusetts General Hospital, Clinical Psychopharmacology Unit, Boston 02114, USA. "Weight gain is associated with the use of many psychotropic medications, including lithium, valproic acid, and several conventional and newer anti-psychotics. Patients asked to select from among several comparable drugs often choose the one least likely to cause weight gain, even if the drug is less effective or has other troublesome adverse effects. For many patients, weight gain is so intolerable that they discontinue treatment. Patients who continue treatment are at risk for clinically significant weight gain that can progress to obesity. Even after patients stop taking the drug, weight gained during therapy may be difficult to lose. Thus, the best approach is to attempt to prevent weight gain when feasible, possibly through pretreatment dietary counseling and judicious drug selection, and to intervene as soon as weight gain becomes evident." · The Journal of the American Medical Association - JAMA - Recombinant Leptin for Weight Loss in Obese and Lean Adults A Randomized, Controlled, Dose-Escalation Trial "Conclusions A dose-response relationship with weight and   fat loss was observed with subcutaneous recombinant leptin injections   in both lean and obese subjects. Based on this study, administration   of exogenous leptin appears to induce weight loss in some obese   subjects with elevated endogenous serum leptin concentrations.   Additional research into the potential role for leptin and related   hormones in the treatment of human obesity is warranted. " · Neurol Psychiatry 2001 "Weight changes during pharmacological treatment are a well-known phenomenon and they have been an object of research since the 1950's. Weight gain occurs during treatment with drugs of different chemical structures and is an important problem when patients are treated with antidepressants, antipsychotics, or mood stabilizers. The clinical relevance of drug-induced weight changes is due to increased rates of morbidity and reduced treatment compliance. Regarding the underlying causes, the important role of neurotransmitter systems and in particular the blockade of serotonin and histamine receptors has been discussed since decades. Only recently, however, research has been started on the effects of psychotropic agents on major neuroendocrine systems involved in appetite and weight regulation. These studies suggest that the fat-cell derived hormone leptin might play an important role. Leptin signals to the brain the size of the adipose tissue and is probably the most important peripheral signal for the long-term regulation of weight. In addition to the neuroendocrine systems, weight gain induced by psychotropic agents might also involve immune modulators, in particular the proinflammatory cytokine tumor-necrosis-factor-alpha (TNF-alpha) and soluble TNF-receptors. Some psychotropic agents influence the TNF system very rapidly, already prior to any obvious increases in weight. Hence, changes in the TNF-alpha system might be of predictive value for drug-induced weight gain. Strategies to minimize or to counteract weight gain induced by psychotropic agents include psychotherapeutic and pharmacological approaches. Although numerous psychotherapeutic approaches are available, they are only of limited usefulness in severely ill psychiatric patients. Fortunately, a number of promising pharmacological approaches to reduce weight have been introduced into clinical practice during the last years; however, so far there is no knowledge on pharmacodynamic and -kinetic interactions with psychotropic drugs, and there is no clinical data on the usefulness and safety of such drug combinations." · Department of Neuroscience, College of Medicine, University of Florida, McKnight Brain Institute, Gainesville, Florida "Ghrelin stimulates and leptin inhibits appetite by modulating neuropeptide Y (NPY) signaling in the hypothalamus. Analysis of plasma ghrelin and leptin by sensitive radioimmunoassays showed that the two peripheral hormones are secreted in pulsatile fashion in rats consuming ad libitum rat chow. Fasting augmented all parameters of ghrelin pulsatile secretion and diminished leptin secretion by selectively attenuating the pulse amplitude; concomitantly it produced synchrony in ghrelin and leptin pulse discharge. These studies imply that a synchronous leptin restraint and ghrelin stimulus on NPYergic signaling may underlie robust appetitive drive." · EFA Sciences LLC, Norwood, Massachusetts "Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of  C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity." · Additional References: Division of Endocrinology, Department of Medicine, Harvard Medical School Glucocorticoids reverse leptin effects on food intake and body fat in mice without increasing NPY and mRNA. Department of Medicine, University of Tennessee College of medicine. Inhibition of cortisol biosynthesis decreases circulating leptin levels in obese humans. Division of Endocrinology, Diabetes and metabolism, Washington University School of Medicine. Hormonal regulation of human leptin in vivo; effects of hydrocortisone and insulin. University of Milan Effect of small dose of dexamethasone on plasma leptin levels in normal obese subjects; a dose-response study. Laboratory of Physiology, University Libre de Bruxelles Metabolic and endocrine effects of sleep deprivation. Concept Therapeutics, Menlo Park, CA. The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats. Neurobiology Division, Department of Cell and Molecular Biology, Tulane University, New Orleans Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration. Department of Clinical Neuroscience, Division of Neurology Huddinge, Karolinska Institute, Stockholm, Sweden, sven.palhagen@karolinska.se. Previously we suggested that major depression (MD) in Parkinson's disease (PD) could be an indication of a more advanced and widespread neurodegenerative process, as PD symptoms were more severe in those with depression. We also found a different antidepressant response with SSRI medication in PD patients with depression compared to depressed patients without PD. This indicates diverse underlying pathophysiological mechanisms. Investigations using single-photon emission computed tomography (SPECT), measuring regional cerebral blood flow (rCBF), may contribute to enlighten the neurobiological substrates linked to depressive symptoms. SPECT was performed in order to compare rCBF in MD patients with and without PD. The study included 11 MD patients with PD, 14 non-depressed PD patients and 12 MD patients without PD. All patients were followed for 12 weeks with repeated evaluation of depressive as well as PD symptoms. Anti-Parkinsonian treatment remained unchanged during the study. Antidepressant treatment with SSRI (citalopram) was given to all patients with MD. SPECT was performed before and after 12 weeks of antidepressant treatment. rCBF was found to differ between PD patients with and without MD, as well as between MD patients with and without PD, both at baseline and concerning the response to treatment with SSRI (citalopram). In patients with PD the rCBF was found to be decreased in preoccipital and occipital regions, a finding more common when PD was combined with MD. In summary, larger cortical areas were found to be involved in depressed PD patients, both with hyperactivity (reciprocal to basal degeneration in PD and maybe dopaminergic treatment) and with hypoactivity (probably due to organic lesions leading to hypoperfusion). These observations support our hypothesis that PD combined with MD is an expression of a more advanced and widespread neurodegenerative disorder. Department of Clinical Neurophysiology, Georg-August-University, Göttingen, Germany. BACKGROUND: Modulation of the serotonergic system affects long-term potentiation (LTP) and long-term depression (LTD), the likely neurophysiologic derivates of learning and memory formation, in animals and slice preparations. Serotonin-dependent modulation of plasticity has been proposed as an underlying mechanism for depression. However, direct knowledge about the impact of serotonin on neuroplasticity in humans is missing. Here we explore the impact of the serotonin reuptake blocker citalopram on plasticity induced by transcranial direct current stimulation (tDCS) in humans in a single-blinded, placebo-controlled, randomized crossover study. METHODS: In 12 healthy subjects, anodal excitability-enhancing or cathodal excitability-diminishing tDCS was applied to the motor cortex under a single dose of 20-mg citalopram or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation (TMS). RESULTS: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for about 60-120 min. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS, whereas it turned cathodal tDCS-induced inhibition into facilitation. CONCLUSIONS: Serotonin has a prominent impact on neuroplasticity in humans, which is in favor for facilitatory plasticity. Taking into account serotonergic hypoactivity in depression, this might explain deficits of learning and memory formation. Moreover, the results suggest that for therapeutic brain stimulation in depression and other neuropsychiatric diseases (e.g., in neurorehabilitation), serotonergic reinforcement may enhance facilitatory aftereffects and thereby increase the efficacy of these tools. Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. AbstractMagnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can provide localised measures of brain chemistry in vivo. We previously found that healthy volunteers receiving the selective serotonin reuptake inhibitor, citalopram, daily for 1 week showed higher levels of a combined measure of glutamate and glutamine (Glx) in occipital cortex than those receiving placebo. The aim of this study was to assess if a similar effect could be detected in the frontal brain region. Twenty-three healthy volunteers randomised to receive either citalopram 20 mg or a placebo capsule daily for 7-10 days were studied and scanned using a 3T Varian INOVA system before and at the end of treatment. Standard short-TE (echo time) PRESS (Point-resolved spectroscopy) (TE = 26 ms) and PRESS-J spectra were acquired from a single 8-cm(3) voxel in a frontal region incorporating anterior cingulate cortex. Glutamate and total Glx levels were quantified both relative to creatine and as absolute levels. Relative to placebo, citalopram produced no change in Glx or glutamate alone at the end of the study. Similarly, no effect was seen on other MRS measures studied: myo-inositol, choline, N-acetylaspartate and creatine. These data suggest that the effects of serotonin reuptake to modify cortical glutamatergic MRS measures may be regionally specific. This supports the potential for MRS in assessing neuroanatomically specific serotonin-glutamate interactions in the human brain. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA. OBJECTIVE: To ascertain the impact of treatment with citalopram on irritability, apathy, delusions, and hallucinations in nondepressed behaviorally disturbed Alzheimer's disease (AD) patients. METHOD: This was a retrospective analysis of data from the 36-week Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease in which patients with probable AD (diagnosed according to criteria of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association [NINCDS/ADRDA]) were treated in a naturalistic manner. Scores were compared on the irritability, apathy, delusions, and hallucinations subscales of the Neuropsychiatric Inventory. The trial was conducted between April 2001 and November 2004. RESULTS: Of the 421 patients enrolled, 44 were started on placebo and were later randomly assigned to citalopram treatment. There were data available for 34 subjects who took placebo for at least 14 days. In this group, there was a 60% reduction in irritability and apathy scores, no effect on scores for delusions, and a clinically insignificant drop in scores for hallucinations. CONCLUSIONS: The use of citalopram was associated with greatly reduced irritability without sedation in a group of behaviorally disturbed patients with AD. © Copyright 2009 Physicians Postgraduate Press, Inc. INSERM, U657, Bordeaux, France. Warnings concerning an increased risk of suicide in patients treated with selective serotonin reuptake inhibitors (SSRIs) re-emerged in early 2003, culminating in the broadcast of a television programme in the UK. In the following months, cumulated proportional reporting ratios showed that the most recently marketed drug, escitalopram, had a much higher proportion of reports of suicide to other adverse drug reactions (ADRs) than the other drugs in the class. To study the reporting patterns over time concerning suicide with the six SSRIs marketed in the UK as of March 2003 and their potential effect on disproportionality signal detection. Monthly cumulated numbers of reports were obtained from the UK Medicines and Healthcare products Regulatory Agency (MHRA), from the time of the first marketing of the drugs concerned and monthly for the 2 months prior to and the 9 months following the broadcast of the television programme (broadcast date: 11 May 2003), and the monthly ratio of suicide to other reports was computed for each SSRI individually and for all SSRIs combined. Of the six SSRIs studied, five (citalopram, paroxetine, fluoxetine, sertraline and venlafaxine) had been marketed for several years and escitalopram for only a few months. At the end of the analysis period, 1.42% (4/281) of all ADR reports for escitalopram were of suicide versus 0.58% for the other five drugs combined (146/25 197). For all SSRIs combined, suicide represented 0.5% (123/24 315) of reports before the broadcast of the television programme, and increased to 2.3% (27/1163) following the programme. For escitalopram, suicide represented 1.1% (1/89) of all ADR reports before the television programme and 1.6% (3/192) afterwards. For the five other drugs combined, suicide represented 0.5% (122/24 226) of ADR reports before the television programme and 2.5% (24/971) afterwards (varying from 1.4% to 4.7% for the various drugs). The post-programme events represented 68% of all reports and 75% of suicides for escitalopram, whereas for older drugs they represented 3.6% of reports and 13% of suicides. For older drugs, the events reported during the high-reporting post-television programme period were diluted by years of low reporting. For escitalopram, although the television programme had little absolute impact on the number of reports, because the drug had been on the market for such a short period of time, a large relative effect was observed. Differential effects related to time on market on cumulated reporting of adverse drug reactions should be taken into account when analysing spontaneous reporting databases with automated signal generation methods after an alert has changed the spontaneous reporting patterns. Proper use of measures of disproportionality requires thorough knowledge of potential biases and careful analysis of reporting patterns. We found no obvious differences between SSRIs once these were taken into account. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Quebec, Canada. The influence of citalopram on regional 5-hydroxytryptamine (serotonin, 5-HT) synthesis, one of the most important presynaptic parameters of serotonergic neurotransmission, was studied. Sprague-Dawley (SPD) rats were used as the controls, and Flinders Resistant Line (FRL) rats were used as auxiliary controls, to hopefully obtain a better understanding of the effects of citalopramon Flinders Sensitive Line (FSL; "depressed") rats. Regional 5-HT synthesis was evaluated using a radiographic method with a labelled tryptophan analog tracer. In each strain of rats, the animals were treated with citalopram (10 mg/(kg day)) or saline for 14 days. The groups consisted of between fourteen and twenty rats. There were six groups of rats with citalopram (CIT) and saline (SAL) groups in each of the strains (SPD-AL, SPD-IT, FRL-AL, FRL-IT, FSL-AL and FSL-IT). A two-factor analysis of variance was used to evaluate the effect of the treatment c., SPD-SAL relative to SPD-CIT) followed by planned comparisons to evaluate the effect in each brain region. In addition, the planned comparison with appropriate contrast was used to evaluate a relative effects in SPD relative to FSL and FRL, and FSL relative to FRL groups. A statistical analysis was first performed in the a priori selected regions, because we had learned, from previous work, that it was possible to select the brain regions in which neurochemical variables had been altered by the disorder and subsequent antidepressant treatments. The results clearly show that citalopram treatment does not have an overall effect on synthesis in the control SPD rats; there was no significant (p > 0.05) difference between the SPD-SAL and SPD-CIT rats. In "depressed" FSL rats, citalopram produced a significant (p < 0.05) elevation of synthesis in seventeen out of thirty-four regions, with a significant (p < 0.05) reduction in the dorsal and median raphe. In the FRL rats, there was a significant (p < 0.05) elevation in the synthesis in twenty-two out of thirty-four brain regions, with a reduction in the dorsal raphe. In addition to these regions magnus raphe was different in the SPD and FSL groups, but it was on the statistical grounds identified as an outlier. There were significant changes produced in the FSL and FRL rats in thirteen out of seventeen a priori selected brain regions, while in the SPD rats, citalopram produced significant changes in only four out of seventeen a priori selected regions. The statistical evaluation also revealed that changes produced by citalopram in the FSL and FRL rats were significantly greater than those in the SPD rats and that there was no significant difference between the effect produced in the FSL and FRL rats. The presented results suggest that in "depressed" FSL rats, the antidepressant citalopram elevates 5-HT synthesis, which probably in part relates to the reported improved in behaviour with citalopram. School of Population Health, University of Queensland, Brisbane, QLD, Australia. a.page@sph.uq.edu.au. OBJECTIVE: To investigate sociodemographic variation in antidepressant utilisation. DESIGN AND SETTING: Cross-sectional analysis of antidepressant prescription under the Pharmaceutical Benefits Scheme in Australia, 2003-2005. MAIN OUTCOME MEASURES: Antidepressant utilisation (defined daily dose/1000/day) by sex, age, socioeconomic status (SES) and geographichal area. RESULTS: Total antidepressant utilisation increased with age. Among those aged >/= 15 years, female utilisation was about double that of males. About half of antidepressant utilisation was accounted for by sertraline, venlafaxine, citalopram, and paroxetine. SES differentials in antidepressant utilisation changed across age groups for males and females: among those aged </= 19 years, total antidepressant utilisation was significantly less in lower SES groups (P < 0.001); there was no relationship to SES among 20-29-year-olds; and among those aged >/= 30 years, antidepressant utilisation was significantly higher in lower SES groups (P < 0.001). SES differences were attenuated after adjusting for urban or rural residence, but remained statistically significant. Antidepressant utilisation rates were highest in regional centres. CONCLUSION: Antidepressant utilisation in Australia partially reflects sociodemographic differences in the prevalence of affective disorder. Discrepancies between treatment provision and treatment need suggest that not all social strata in Australia have equal access to these treatments. INSERM, U657, Bordeaux, France. Warnings concerning an increased risk of suicide in patients treated with selective serotonin reuptake inhibitors (SSRIs) re-emerged in early 2003, culminating in the broadcast of a television programme in the UK. In the following months, cumulated proportional reporting ratios showed that the most recently marketed drug, escitalopram, had a much higher proportion of reports of suicide to other adverse drug reactions (ADRs) than the other drugs in the class. To study the reporting patterns over time concerning suicide with the six SSRIs marketed in the UK as of March 2003 and their potential effect on disproportionality signal detection. Monthly cumulated numbers of reports were obtained from the UK Medicines and Healthcare products Regulatory Agency (MHRA), from the time of the first marketing of the drugs concerned and monthly for the 2 months prior to and the 9 months following the broadcast of the television programme (broadcast date: 11 May 2003), and the monthly ratio of suicide to other reports was computed for each SSRI individually and for all SSRIs combined. Of the six SSRIs studied, five (citalopram, paroxetine, fluoxetine, sertraline and venlafaxine) had been marketed for several years and escitalopram for only a few months. At the end of the analysis period, 1.42% (4/281) of all ADR reports for escitalopram were of suicide versus 0.58% for the other five drugs combined (146/25 197). For all SSRIs combined, suicide represented 0.5% (123/24 315) of reports before the broadcast of the television programme, and increased to 2.3% (27/1163) following the programme. For escitalopram, suicide represented 1.1% (1/89) of all ADR reports before the television programme and 1.6% (3/192) afterwards. For the five other drugs combined, suicide represented 0.5% (122/24 226) of ADR reports before the television programme and 2.5% (24/971) afterwards (varying from 1.4% to 4.7% for the various drugs). The post-programme events represented 68% of all reports and 75% of suicides for escitalopram, whereas for older drugs they represented 3.6% of reports and 13% of suicides. For older drugs, the events reported during the high-reporting post-television programme period were diluted by years of low reporting. For escitalopram, although the television programme had little absolute impact on the number of reports, because the drug had been on the market for such a short period of time, a large relative effect was observed. Differential effects related to time on market on cumulated reporting of adverse drug reactions should be taken into account when analysing spontaneous reporting databases with automated signal generation methods after an alert has changed the spontaneous reporting patterns. Proper use of measures of disproportionality requires thorough knowledge of potential biases and careful analysis of reporting patterns School of Social Policy and Practice, University of Pennsylvania, Philadelphia, PA, USA. OBJECTIVE: This study examined the pharmacologic, clinical, and demographic factors associated with switching antidepressants during the first three months of outpatient treatment for episodes of depression. METHODS: A cohort analysis of outpatients aged 18-75 and treated for a depressive disorder (N=56,521) was performed with PharMetrics administrative data from 2001-2006. Patients commencing antidepressant treatment who continued to receive the initial antidepressant or a second antidepressant for > or = 72 of the first 90 days were selected. Antidepressant switching was defined as prescription of a second antidepressant within 90 days of the first antidepressant prescription and continuation of the second antidepressant for > or = 15 days after termination of the first antidepressant. RESULTS: Overall, 8.6% of patients switched antidepressants during the first 90 days of treatment. The highest rates of switching were among patients initiating trazodone (47.4%), tricyclic antidepressants (26.6%), and mirtazapine (17.2%); the lowest switching rates occurred after starting venlafaxine (6.5%) or sertraline (7.4%). Antidepressant switching was significantly related to recent emergency mental health treatment (adjusted odds ratio [AOR]=1.7, 99% confidence interval [CI]=1.3-2.2); treatment of major depressive disorder versus other depressive disorders (AOR=1.4, CI=1.3-1.5), especially severe major depressive episodes (AOR=1.6, CI=1.4-1.9); and inversely related to moderately high versus low initial antidepressant dose (AOR=.7, CI=.6-.8). Several other patient characteristics were significant but less powerful predictors of antidepressant switching. CONCLUSIONS: Among adults with depression starting antidepressant therapy, medication switching commonly occurs during the first three months of treatment. Greater clinical severity and low initial dosing may increase the risk of switching antidepressants. Determining optimal approaches for weight maintenance: a randomized controlled trial. BACKGROUND: Weight regain often occurs after weight loss in overweight individuals. We aimed to compare the effectiveness of 2 support programs and 2 diets of different macronutrient compositions intended to facilitate long-term weight maintenance. METHODS: Using a 2 x 2 factorial design, we randomly assigned 200 women who had lost 5% or more of their initial body weight to an intensive support program (implemented by nutrition and activity specialists) or to an inexpensive nurse-led program (involving "weigh-ins" and encouragement) that included advice about high-carbohydrate diets or relatively high-monounsaturated-fat diets. RESULTS: In total, 174 (87%) participants were followed-up for 2 years. The average weight loss (about 2 kg) did not differ between those in the support programs (0.1 kg, 95% confidence interval [CI] -1.8 to 1.9, p = 0.95) or diets (0.7 kg, 95% CI -1.1 to 2.4, p = 0.46). Total and low-density lipoprotein (LDL) cholesterol levels were significantly higher among those on the high-monounsaturated-fat diet (total cholesterol: 0.17 mmol/L, 95% CI 0.01 to 0.33; p = 0.040; LDL cholesterol: 0.16 mmol/L, 95% CI 0.01 to 0.31; p = 0.039) than among those on the high- carbohydrate diet. Those on the high-monounsaturated-fat diet also had significantly higher intakes of total fat (5% total energy, 95% CI 3% to 6%, p < 0.001) and saturated fat (2% total energy, 95% CI 1% to 2%, p < 0.001). All of the other clinical and laboratory measures were similar among those in the support programs and diets. INTERPRETATION: A relatively inexpensive program involving nurse support is as effective as a more resource-intensive program for weight maintenance over a 2-year period. Diets of different macronutrient composition produced comparable beneficial effects in terms of weight loss maintenance. ClinicalTrials.gov trial register no. Seizure control and biochemical profile on the ketogenic diet in young children with refractory epilepsy-Indian experience. Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. AIM: This study evaluated the efficacy and tolerability of the ketogenic diet (KD) in young Indian children with refractory epilepsy. The changes in biochemical and lipid profile with KD were also assessed. METHODS: Children aged 6 months to 5 years who had daily seizures (or at least 7 seizures/week) despite the appropriate use of at least three antiepileptic drugs were enrolled. KD was introduced using a non-fasting gradual initiation protocol. Seizure frequency, biochemical profile (liver and kidney function tests, fasting lipid profile, and spot urinary calcium-creatinine ratio) and adverse effects were recorded. Patients continuing KD were followed up for a minimum period of 12 months. RESULTS: Twenty-seven children were enrolled. Non-fasting gradual KD initiation was well tolerated. Eighty-eight percent remained on KD at 3 months, 55% remained on KD at 6 months, and 37% remained on it at 1 year. Intention-to-treat analysis revealed that 48% (13 of 27) had >50% reduction in seizures, and four children (15 %) were seizure free at 6 months. At 1 year, 37% had >50% reduction in seizures and five children (18.5%) were seizure free. Adverse effects included constipation (74%), weight loss (14.8%), edema due to hypo-albuminemia (7.4%) and renal stones (3.7%). Biochemical profile did not reveal significant changes over time, except for reduced serum albumin and increased spot urinary calcium-creatinine ratio. CONCLUSION: KD is an effective and well- tolerated treatment option in young Indian children with refractory epilepsy. However, careful ongoing medical supervision is needed. Effect of CLA isomers and their mixture on aging C57Bl/6J mice. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. BACKGROUND: Dietary supplements containing conjugated linoleic acid (CLA) are widely promoted for weight loss management over the counter. Recently, FDA approved the CLA as Generally Recognized as Safe category so that it can be used in various food and beverages. The combined effect of CLA isomers have been studied extensively in animals and humans, however, the role of individual isomers remains unraveled. AIM: The present investigation addresses the effects of CLA isomers on body composition and body weight as well as safety using female C57Bl/6J aging mice. METHODS: Two main CLA isomers and their mixture were fed to 12-months-old female C57Bl/6J mice. Ten percent corn oil (CO) based fat diet supplemented with 0.5% purified cis 9 trans 11 (c9,t11) CLA or trans 10 cis 12 (t10,c12) CLA or their mixture (CLA mix, 50:50) for 6 months. The lean mass, fat mass, glucose, non-esterified fatty acids, and insulin were examined at the end of study. RESULTS: As a result of 6 months dietary intervention, both t10,c12 CLA and CLA mix groups showed increased lean mass and reduced fat mass compared to that of c9,t11 CLA and CO group. However, insulin resistance and liver hypertrophy were observed in t10,c12 CLA and CLA mix groups based on the results of homeostasis model assessment, revised quantitative insulin-sensitivity check index (R-QUICKI), intravenous glucose tolerance test, and liver histology. Liver histology revealed that increased liver weight was due to hypertrophy. CONCLUSION: In conclusion, the major CLA isomers have a distinct effect on fat mass, glucose, and insulin metabolism. The t10,c12 isomer was found to reduce the fat mass and to increase the lean mass but significantly contributed to increase insulin resistance and liver hypertrophy, whereas c9,t11 isomer prevented the insulin resistance. Between the two major CLA isomers, the t10,c12 was attributed to reduce fat mass whereas, c9,t11 improves the insulin sensitivity. Obesity and restless legs syndrome in men and women. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. xiang.gao@channing.harvard.edu BACKGROUND: Obesity and restless legs syndrome (RLS) are both associated with hypofunction of dopamine in the CNS. We therefore examined whether individuals who are obese have an increased risk of RLS in two ongoing US cohorts, the Nurses' Health Study II and the Health Professional Follow-up Study. METHODS: We included 65,554 women and 23,119 men free of diabetes, arthritis, and pregnancy in the current analyses. Information on RLS was assessed using a set of standardized questions. Participants were considered to have RLS if they met four RLS diagnostic criteria recommended by the International RLS Study Group and had restless legs > or =5 times/month. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic regression models adjusting for age, smoking, use of antidepressant, phobic anxiety score, and other covariates. Log ORs from the two cohorts were pooled by a fixed-effects model. RESULTS: There were 6.4% of women and 4.1% of men who were considered to have RLS. Multivariate adjusted ORs for RLS were 1.42 (95% CI: 1.3, 1.6; p trend <0.0001) for participants with body mass index (BMI) >30 vs <23 kg/m(2) and 1.60 (95% CI: 1.5, 1.8; p trend <0.0001) for highest vs lowest waist circumference quintiles. Greater BMI in early adulthood (age 18-21 years) and weight gain were also associated with a higher prevalence of RLS (p trend <0.01 for both). CONCLUSIONS: Both overall and abdominal adiposity are associated with increased likelihoods of having restless legs syndrome (RLS). Further prospective studies are warranted to clarify causative association between obesity and risk of developing RLS. 2009 Apr 7;72(14):1255-61. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany. frank.andersohn@charite.de OBJECTIVE: Use of antidepressants has been reported to cause considerable weight gain. The aim of this study was to assess the risk of diabetes mellitus associated with antidepressant treatment and to examine whether the risk is influenced by treatment duration or daily dose. METHOD: This was a nested case-control study in a cohort of 165,958 patients with depression who received at least one new prescription for an antidepressant between January 1, 1990, and June 30, 2005. Data were from from the U.K. General Practice Research Database. Patients were at least 30 years of age and without diabetes at cohort entry. RESULTS: A total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. Compared with no use of antidepressants during the past 2 years, recent long-term use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio=1.84, 95% CI=1.35-2.52). The magnitude of the risk was similar for long-term use of moderate to high daily doses of tricyclic antidepressants (incidence rate ratio=1.77, 95% CI=1.21-2.59) and selective serotonin reuptake inhibitors (incidence rate ratio=2.06, 95% CI=1.20-3.52). Treatment for shorter periods or with lower daily doses was not associated with an increased risk. CONCLUSIONS: Long-term use of antidepressants in at least moderate daily doses was associated with an increased risk of diabetes. This association was observed for both tricyclic antidepressants and selective serotonin reuptake inhibitors. 2009 May;166(5):591-8. Epub 2009 Apr 1. A proof of concept randomised placebo controlled factorial trial to examine the efficacy of St John's wort for smoking cessation and chromium to prevent weight gain on smoking cessation. Primary Care Clinical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. a.c.parsons@bham.ac.uk BACKGROUND: St John's wort is an effective antidepressant that can reduce tobacco withdrawal symptoms, but it is not known whether it assists cessation. Chromium assists weight loss and might limit post cessation weight gain. METHODS: In a factorial design, we randomised smokers stopping smoking to 900 mg St John's wort (SJW) active or placebo and also randomised them to 400 microm chromium or placebo daily. Treatment started 2 weeks prior to quit day and continued for 14 weeks. Participants and researchers were blind to treatment allocation. All participants received weekly behavioural support. The primary endpoints were biochemically confirmed prolonged abstinence and mean weight gain in abstinent smokers 4 weeks after quitting. RESULTS: 6/71 (8.5%) participants on active SJW and 9/72 (12.5%) on placebo achieved prolonged abstinence at 4 weeks, an odds ratio (OR) (95% confidence interval) of 0.65 (0.22-1.92). At 6 months, 3 (4.2%) SJW active and 6 (8.3%) SJW placebo participants were still abstinent, an OR of 0.49 (0.12-2.02). Among these participants, the mean difference in weight gain between active chromium and placebo was -0.8 1kg (-3.79 to 2.18) at 4 weeks and -3.88 kg (-12.13 to 4.38) at 6 months. CONCLUSIONS: Taking together the absolute quit rates, the small difference between active and placebo, and lack of effects on withdrawal shows that SJW is ineffective for smoking cessation. Insufficient people stopped smoking to properly test the efficacy of chromium in preventing weight gain, but the point estimate indicates a potentially worthwhile benefit. 2009 Jun 1;102(1-3):116-22. Epub 2009 Mar 27. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Women's Behavioral HealthCARE and the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, 3811 O'Hara St., Pittsburgh, PA 15213, USA. wisnerkl@upmc.edu OBJECTIVE: Selective serotonin reuptake inhibitor (SSRI) use during pregnancy incurs a low absolute risk for major malformations; however, other adverse outcomes have been reported. Major depression also affects reproductive outcomes. This study examined whether 1) minor physical anomalies, 2) maternal weight gain and infant birth weight, 3) preterm birth, and 4) neonatal adaptation are affected by SSRI or depression exposure. METHOD: This prospective observational investigation included maternal assessments at 20, 30, and 36 weeks of gestation. Neonatal outcomes were obtained by blinded review of delivery records and infant examinations. Pregnant women (N=238) were categorized into three mutually exclusive exposure groups: 1) no SSRI, no depression (N=131); 2) SSRI exposure (N=71), either continuous (N=48) or partial (N=23); and 3) major depressive disorder (N=36), either continuous (N=14) or partial (N=22). The mean depressive symptom level of the group with continuous depression and no SSRI exposure was significantly greater than for all other groups, demonstrating the expected treatment effect of SSRIs. Main outcomes were minor physical anomalies, maternal weight gain, infant birth weight, pregnancy duration, and neonatal characteristics. RESULTS: Infants exposed to either SSRIs or depression continuously across gestation were more likely to be born preterm than infants with partial or no exposure. Neither SSRI nor depression exposure increased risk for minor physical anomalies or reduced maternal weight gain. Mean infant birth weights were equivalent. Other neonatal outcomes were similar, except 5-minute Apgar scores. CONCLUSIONS: For depressed pregnant women, both continuous SSRI exposure and continuous untreated depression were associated with preterm birth rates exceeding 20%. 2009 May;166(5):557-66. Epub 2009 Mar 16 An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9119, USA. madhukar.trivedi@utsouthwestern.edu OBJECTIVE: To evaluate the efficacy of olanzapine/fluoxetine combination (OFC) versus olanzapine or fluoxetine monotherapy across all clinical trials of treatment-resistant depression sponsored by Eli Lilly and Company. METHOD: Efficacy and safety data from 1146 patients with a history of nonresponse during the current depressive episode who subsequently exhibited nonresponse during a 6- to 8- week antidepressant open-label lead-in phase and were randomly assigned to OFC (N = 462), fluoxetine (N = 342), or olanzapine (N = 342) for double-blind treatment were analyzed. All patients had a diagnosis of major depressive disorder as defined by DSM-III or DSM- IV criteria. The dates in which the trials were conducted ranged from May 1997 to July 2005. RESULTS: After 8 weeks, OFC patients demonstrated significantly greater Montgomery-Asberg Depression Rating Scale improvement (mean change = -13.0) than fluoxetine (- 8.6, p < .001) or olanzapine (-8.2, p < .001) patients, via a mixed-effects model repeated-measures analysis. Remission rates were 25.5% for OFC, 17.3% (p = .006) for fluoxetine, and 14.0% (p < .001) for olanzapine. Adverse events in >or= 10% of OFC patients were weight gain, increased appetite, dry mouth, somnolence, fatigue, headache, and peripheral edema. Random glucose mean change (mg/dL) was +7.92 for the OFC group, +1.62 for the fluoxetine group (p = .020), and +9.91 for the olanzapine group (p = .485). Random cholesterol mean change (mg/dL) was +12.4 for OFC, +2.3 for fluoxetine (p < .001), and +3.1 for olanzapine (p < .001); incidence of treatment-emergent increase from normal to high cholesterol (baseline < 200 mg/dL and >or= 240 subsequently) was significantly higher for the OFC group (10.2%) than for the fluoxetine group (3.1%, p = .017) but not the olanzapine group (8.0%, p = .569). Mean weight change (kg) was +4.42 for OFC, -0.15 for fluoxetine (p < .001), and +4.63 for olanzapine (p = .381), with 40.4% of OFC patients gaining >or= 7% body weight (vs. olanzapine: 42.9%, p = .515; fluoxetine: 2.3%, p < .001). CONCLUSION: Results of this analysis showed that OFC-treated patients experienced significantly improved depressive symptoms compared with olanzapine- or fluoxetine- treated patients following failure of 2 or more antidepressants within the current depressive episode. Safety results for OFC were generally consistent with those for its component monotherapies. The total cholesterol increase associated with OFC was more pronounced than with olanzapine alone. 2009 Mar;70(3):387-96. Epub 2009 Mar 10 Antidepressant phenelzine alters differentiation of cultured human and mouse preadipocytes. Institut National de la Santé et de la Recherche Médicale U693, University Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France. Change in body weight is a frequent side effect of antidepressants and is considered to be mediated by central effects on food intake and energy expenditure. The antidepressant phenelzine (Nardil) potently inhibits both monoamine oxidase and semicarbazide-sensitive amine oxidase activities, two enzymes that are highly expressed in adipose tissue, raising the possibility that it could directly alter adipocyte biology. Treatment with this compound is rather associated with weight gain. The aim of this work was to examine the effects of phenelzine on differentiation and metabolism of cultured human and mouse preadipocytes and to characterize the mechanisms involved in these effects. In all preadipocyte models, phenelzine induced a time- and dose-dependent reduction in differentiation and triglyceride accumulation. Modulation of lipolysis or glucose transport was not involved in phenelzine action. This effect was supported by the reduced expression in the key adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein-alpha, which was observed only at the highest drug concentrations (30-100 microM). The PPAR- gamma agonists thiazolidinediones did not reverse phenelzine effects. By contrast, the reduction in both cell triglycerides and sterol regulatory element-binding protein-1c (SREBP-1c) was detectable at lower phenelzine concentrations (1-10 microM). Phenelzine effect on triglyceride content was prevented by providing free fatty acids to the cells and was partially reversed by overexpression of a dominant-positive form of SREBP-1c, showing the privileged targeting of the lipogenic pathway. When considered together, these findings demonstrate that an antidepressant directly and potently inhibits adipocyte lipid storage and differentiation, which could contribute to psychotropic drug side effects on energy homeostasis. 2009 May;75(5):1052-61. Epub 2009 Feb 6 Adjunctive aripiprazole in major depressive disorder: analysis of efficacy and safety in patients with anxious and atypical features. UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9119, USA. Madhukar.Trivedi@UTSouthwestern.edu OBJECTIVE: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline. METHOD: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score > or = 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737). RESULTS: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p < or = .001; nonanxious: -8.61 vs. -4.97, p < or = .001; atypical: -9.31 vs. -5.15, p < or = .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups. CONCLUSION: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758. Copyright 2008 Physicians Postgraduate Press, Inc. 2008 Dec;69(12):1928-36. Epub 2008 Dec 2 Efficacy, safety and tolerability of quetiapine augmentation in treatment resistant depression: An open-label, pilot study. Manchester Mental Health and Social Care Trust/University of Manchester M13 9WL, United Kingdom. BACKGROUND: Atypical antipsychotics may have efficacy as augmentation therapy in treatment resistant depression (TRD) but evidence is limited. METHODS: An open label study of quetiapine augmentation in 24 patients (mean age: 46.3 years) with a DSM-IV major depressive episode resistant to at least 2 trials of antidepressant medication, and currently taking a monoamine reuptake inhibitor. An 8-week treatment phase was followed by an 18-week extension in patients who showed clinical benefit. RESULTS: Eighteen patients (75%) completed the 8-week treatment phase with seven patients (29%) being responders on the Montgomery Asberg Depression Rating Scale and 13 (54%) on the CGI-I. Fewer patients responded if they had previously received olanzapine in the current episode but this was not statistically significant (0% v 37%, p=0.27). Of the eleven patients entering the extension phase, 3 patients (27%) experienced a significant worsening of mood. The most common adverse events were sedation (54%), dry mouth (38%) and dizziness (29%). Significant weight gain was found in 40% of patients treated for 26 weeks. Average quetiapine doses were 245 mg at 8 weeks and 346 mg at 26 weeks. CONCLUSIONS: Quetiapine may be a helpful adjunctive agent for some patients with TRD but placebo-controlled trials are needed to establish its place in management. LIMITATIONS: The trial was open-label and the numbers were small. 2009 Jan 24. [Epub ahead of print] Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial. Catholic University of Sacred Heart of Rome, Institute of Psychiatry and Psychology, Bipolar Disorders Unit, Via Ugo De Carolis, 48 00136 Roma, Italy. mariannamazza@hotmail.com OBJECTIVE: Several lines of research suggested that aripiprazole might be a useful treatment for acute bipolar depression. The aim of this open-label trial is to give more evidence of the clinical effectiveness and tolerability of aripiprazole in acute bipolar depression. RESEARCH DESIGN AND METHODS: Aripiprazole response was prospectively assessed for 16 weeks using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Severity Scale (CGI-S), and the Young Mania Rating Scale in 85 bipolar patients with acute depression inadequately responsive to one mood stabilizer. MAIN OUTCOME MEASURES: Aripiprazole was well tolerated. Only three (3.5%) patients discontinued the study for side effects. The most common side effect was akathisia, occurring in 17/80 (21.2%) patients. Patients showed statistically insignificant weight gain (0.9 +/- 2.64 kg) over the 16-week trial. RESULTS: Patients showed a significant decrease in mean MADRS and CGI-S, and 80 (94.1%) patients completed the 16-week trial. Thirty-nine (45.8%) patients received aripiprazole as monotherapy and 46 received the drug adjunctively (54.1%). Fifty-two (65%) patients met criteria for response (>/= 50% reduction in MADRS total score), 30 (37.5%) patients met criteria for remission (final MADRS total score </= 12). CONCLUSIONS: Aripiprazole was associated with beneficial effects on mood in patients with bipolar depression, and appears well tolerated with very small changes in mean body weight. These results highlight the potential benefits of aripiprazole for bipolar disorder patients. However, double-blind, placebo-controlled studies are necessary to confirm aripiprazole's efficacy, tolerability and safety in bipolar depression. 2008 Dec;9(18):3145-9 Quality improvement in long term care: the psychotropic assessment tool (PAT). Washington University, Barnes Jewish Hospital, St. Louis, MO, USA. BACKGROUND: There are already a substantial number of individuals with dementia in long-term care. Many nursing home patients have difficult behaviors and are currently managed with psychotropic medications. Medications for behavior need to be titrated and monitored over time for efficacy and safety, and subsequently tapered if ineffective. Some of these medications are not without risk, and that risk-benefit ratio should be discussed and documented with the family. Currently, we are not aware of any quality improvement process that has been developed in long-term care to address these issues. OBJECTIVES: To describe the process of a novel quality improvement intervention that was designed to improve documentation in the medical record and interdisciplinary communication of the usefulness and possible side effects of psychotropic agents used in the management of difficult behaviors for dementia. DESIGN: Retrospective review of the chart and quality improvement records in a long-term care facility. SETTING: An academic long-term care facility that specializes in dementia care in St. Louis, MO. METHODS: The quality improvement team created a process and a form named the Psychotropic Assessment Tool (PAT) to document current behavioral symptoms of the residents; determine whether the resident was on psychotropic agents; identify whether agents had been initiated, titrated, and/or tapered if appropriate; and whether there were any side effects related to the behavioral medications. A letter was created and provided to the surrogate decision maker that described the risk-benefit ratio of the use of antipsychotic agents when these drugs were prescribed. Recommendations from the quality improvement team were provided to the primary care physician. After 1 year of this process, we reviewed the medical charts and quality improvement PAT forms of all residents. We documented the use of psychotropic agents before and after initiating the PAT process, the presence of current behavioral symptoms, the presence of possible side effects, and the recommendations of the interdisciplinary team that met after the monthly quality improvement meetings. RESULTS: A total of 110 patients were included in this study, which reviewed psychotropic drug use between July 2005 and July 2006. The mean age of the residents was 83.8 +/- 7.5 years. All residents had a diagnosis of dementia. Mean MMSE score was 13.5 +/- 7.3. The prevalence of potential problems that could have been associated with psychotropic drug use was not insignificant and included falls (45%), weight loss (16%), weight gain (7%), dizziness (9%), and sedation (5%). However, behaviors that might warrant psychotropic drug use were not uncommon and included active depression (12%), anxiety (24%), hallucinations (11%), disruptive behavior (21%) and delusions (21%). The percentage of residents on antipsychotics changed from 26.5% pre-PAT process to 25.2% post-PAT process; those on anxiolytics changed from 6.0% to 4.0%. There was a change in hypnotics from 2.6% to 3.4%. Antidepressant usage remained the same at 55%. The PAT CHAT discussion resulted in recommendation of medication changes in 25% of residents. CONCLUSIONS: The initiation of this quality improvement process using the PAT led to improved chart documentation and interdisciplinary communication between the team, primary care physicians, and families. Further studies are needed to determine whether this process can impact use of psychotropic agents, improve quality of life, decrease adverse drug events, and/or reduce medical-legal risk. 2008 Nov;9(9):676-83. Epub 2008 Sep 27 Psychotropic prescription practices in east Asia: looking back and peering ahead. Department of Pharmacology, National University of Singapore, Singapore. phctanch@nus.edu.sg PURPOSE OF REVIEW: The present review focuses on the pharmacoepidemiological issues of psychotropic drug use in countries within east Asia, with special emphasis on antipsychotic, antidepressant and benzodiazepine prescriptions. Pharmacogenetic studies in different ethnic groups are also reviewed. RECENT FINDINGS: Recent studies have revealed the prevalence of antipsychotic polytherapy (defined as the use of more than one antipsychotic; up to 45.7%), less conservative antipsychotic use (defined as the use of more than 1000 mg/day chlorpromazine equivalents; up to 17.9%) and depot antipsychotic use (up to 15.3%) in different populations in east Asia. Clozapine is commonly prescribed (up to 60%) in China. There is a trend of increasing second-generation antipsychotic use in east Asian countries. Up to 67.5% of patients received newer antidepressants such as selective serotonin reuptake inhibitors. Benzodiazepine medications are used in up to 29.9% of study populations. Socioeconomic factors appear to be one of the major common factors that affect the prescription of antipsychotics and newer antidepressants. Pharmacogenetic factors associated with antipsychotic response, weight gain and extrapyramidal side effects have been examined. Treatment adherence and pharmacoeconomic factors are relatively understudied. SUMMARY: Future studies on prescribing trends of antipsychotics and antidepressants need to focus on children, adolescent and elderly patient populations, the impact of changing prescription trends and the long-term effects on patients and their caregivers, as well as pharmacogenetic factors, which can potentially pave the way for better and more individualized prescription of psychotropic drugs in east Asia. 2008 Nov;21(6):645-50 Changing trends in pediatric antipsychotic use in Florida's Medicaid program. Department of Mental Health Law and Policy, Louis de la Parte Florida Mental Health Institute, University of South Florida, Tampa, FL 33647, USA. rconstantine@fmhi.usf.edu OBJECTIVE: This study describes the changing trends in antipsychotic use among youths aged 18 years and younger and in age subgroups (zero to five, six to 12, and 13 to 18 years) in the Florida Medicaid program. METHODS: The study used Florida Medicaid claims data associated with approximately 1.2 million children and adolescent enrollees per year to describe monthly antipsychotic use from July 2002 to December 2005. A preliminary examination of trends indicated that antipsychotic use might be different for the periods before May 2004 and after April 2004. For this reason, piecewise regression was used to compare the trends for these two periods. RESULTS: This study found significant increases in the use of antipsychotic medications for all three age groups from July 2002 to April 2004. The greatest rate of growth was for the 13- to 18-year age group, and the least rate of growth was for the zero- to five-year age group. From May 2004 to December 2005 antipsychotic utilization trends were flat for youths age 18 years and younger and for the six- to 12-year and the 13- to 18-year age groups. For preschool-age children (the zero- to five-year age group), there was a slight but significant decline in antipsychotic use. Significant changes were also observed in the specific second-generation antipsychotic agents prescribed. Although risperidone remained the most frequently prescribed antipsychotic, its use declined significantly from May 2004 to December 2005. Olanzapine use also declined during this period. On the other hand, aripiprazole use increased significantly throughout the study period, with usage among the 13- to 18-year age group almost equaling that of risperidone by December 2005. CONCLUSIONS: The lack of growth in antipsychotic prescribing after the spring of 2004 represents a significant departure from historical trends. Although some in-state policies may have affected these trends, it appears that the timing and extent of the changes occurred shortly after the Food and Drug Administration required warnings on second-generation antipsychotic medications related to weight gain, glucose levels, and diabetes. They appeared immediately after the black box warning for pediatric antidepressant medications, and they appeared shortly after the Joint American Diabetes and American Psychiatric Association Consensus Statement. These factors suggest the existence of a prescribing community that is responsive to evidence and to professional and regulatory actions based on it. 2008 Oct;59(10):1162-8 Probiotics Improve Outcomes After Roux-en-Y Gastric Bypass Surgery: A Prospective Randomized Trial. Department of Surgery, Surgery Center for Outcomes Research and Evaluation (SCORE), Stanford University School of Medicine, Stanford, CA, USA. INTRODUCTION: Roux-en-Y gastric bypass (RNYGB) surgery offers an effective and enduring treatment for morbid obesity. Gastric bypass may alter gastrointestinal (GI) flora possibly resulting in bacterial overgrowth and dysmotility. Our hypothesis was that daily use of probiotics would improve GI outcomes after RNYGB. METHODS: Forty-four patients undergoing RNYGB were randomized to either a probiotic or control group; 2.4 billion colonies of Lactobacillus were administered daily postoperatively to the probiotic group. The outcomes of H(2) levels indicative of bacterial overgrowth, GI-related quality of life (GIQoL), serologies, and weight loss were measured preoperatively and at 3 and 6 months postoperatively. Categorical variables were analyzed by chi (2) test and continuous variables were analyzed by t test with a p < 0.05 for significance. RESULTS: At 6 months, a statistically significant reduction in bacterial overgrowth was achieved in the probiotic group with a preoperative to postoperative change of sum H( 2 ) part per million (probiotics = - 32.13, controls = 0.80). Surprisingly, the probiotic group attained significantly greater percent excess weight loss than that of control group at 6 weeks (controls = 25.5%, probiotic = 29.9%) and 3 months (38.55%, 47.68%). This trend also continued but was not significant at 6 months (60.78%, 67.15%). The probiotic group had significantly higher postoperative vitamin B12 levels than the control group. Both probiotic and control groups significantly improved their GIQoL. CONCLUSION: In this novel study, probiotic administration improves bacterial overgrowth, vitamin B12 availability, and weight loss after RNYGB. These data may provide further evidence that altering the GI microbiota can influence weight loss. Probiotic administration alters the gut flora and attenuates colitis in mice administered dextran sodium sulfate. Department of Gastrointestinal Sciences, The Wellcome Trust Research Laboratory, Christian Medical College, Vellore, India. BACKGROUND: Probiotics are used in the therapy of inflammatory bowel disease. This study aimed to determine whether prior administration of probiotic lactobacilli and bifidobacteria would prevent disease and change gut flora in an animal model of colitis. METHODS: Swiss albino mice received a probiotic mixture (four Lactobacillus and four Bifidobacterium species) or medium (control) for a week prior to induction of colitis by oral 4% dextran sodium sulfate (DSS) for seven days. Appropriate non-colitis controls were used. Histological damage was assessed (n = 5 per group), as was expression of mRNA for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta1 and SOCS-1 in the colonic mucosa (n = 6 per group). Secretion of TNF-alpha was measured in distal colon organ culture (n = 5-6 per group). Levels of Bacteroides, Bifidobacterium, and Lactobacillus acidophilus in feces were quantified by real time polymerase chain reaction (PCR) targeting 16S rDNA. RESULTS: Compared to untreated DSS colitis, probiotic treatment significantly reduced weight loss (P < 0.05), shifted histological damage to lesser grades of severity (P < 0.001), reduced mRNA expression of TNF-alpha and TGF-beta1 (P < 0.05), and down-regulated production of TNF-alpha from distal colon explants (P < 0.05). Colitis induced a significant reduction in the relative proportions of Bifidobacterium, Bacteroides and Lactobacillus acidophilus group bacteria in feces, and these levels were significantly increased in probiotic-treated mice compared to DSS mice (P < 0.001). CONCLUSION: Prior administration of probiotic bacteria reduced mucosal inflammation and damage in DSS-induced colitis. DSS colitis was associated with significant changes in the fecal anaerobic bacterial flora and these changes were modulated by administration of probiotic bacteria. Biotherapeutic effects of Bifidobacterium spp. on orogastric and systemic candidiasis in immunodeficient mice. Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, Wisconsin, USA. balish@surgery.wisc.edu. Two commercially available Bifidobacterium spp. (Bifidobacterium infantis and Bifidobacterium lactis) were compared for their capacities to protect immunodeficient bg/bg-nu/nuand bg/bg-nu/+mice from orogastric and lethal candidiasis. Both Bifidobacterium spp. prolonged the survival of Candida albicans-colonized adult and neonatal bg/bg-nu/numice. The bifidobacteria affected the production of antibodies to C. albicans, inhibited disseminated candidiasis, suppressed weight loss associated with C. albicans infection, inhibited the growth of C. albicans in the alimentary tract, inhibited systemic candidiasis of endogenous origin, and decreased the severity of gastric candidiasis in both mouse strains. B. infantis inhibited systemic candidiasis of endogenous origin better than B. lactis; however, B. lactis was significantly more effective at inhibiting C. albicans colonization of the alimentary tract, suppressing gastric candidiasis, and protecting bg/bg-nu/numice from lethal candidiasis than B. infantis. These results show that Bifidobacterium spp. can protect immunodeficient mice from candidiasis but different species manifest quantitative and qualitative differences in their probiotic and biotherapeutic effects. Saccharomyces boulardii ameliorates Citrobacter rodentium-induced colitis through actions on bacterial virulence factors. Div. of Gastroenterology, BC Children's Hospital, 4480 Oak St., Rm. K4-181, Vancouver, BC, Canada V6H 3V4. Saccharomyces boulardii has received increasing attention as a probiotic effective in the prevention and treatment of infectious and inflammatory bowel diseases. The aim of this study was to examine the ameliorating effects of S. boulardii on Citrobacter rodentium colitis in vivo and identify potential mechanisms of action. C57BL/6 mice received 2.5 x 10(8) C. rodentium by gavage on day 0, followed by S. boulardii (25 mg; 5 x 10(8) live cells) gavaged twice daily from day 2 to day 9. Animal weights were monitored until death on day 10. Colons were removed and assessed for epithelial barrier function, histology, and myeloperoxidase activity. Bacterial epithelial attachment and type III secreted proteins translocated intimin receptor Tir (the receptor for bacterial intimin) and EspB (a translocation apparatus protein) required for bacterial virulence were assayed. In infected mice, S. boulardii treatment significantly attenuated weight loss, ameliorated crypt hyperplasia (234.7 +/- 7.2 vs. 297.8 +/- 17.6 microm) and histological damage score (0.67 +/- 0.67 vs. 4.75 +/- 0.75), reduced myeloperoxidase activity (2.1 +/- 0.4 vs. 4.7 +/- 0.9 U/mg), and attenuated increased mannitol flux (17.2 +/- 5.0 vs. 31.2 +/- 8.2 nm.cm(-2).h(-1)). The ameliorating effects of S. boulardii were associated with significantly reduced numbers of mucosal adherent C. rodentium, a marked reduction in Tir protein secretion and translocation into mouse colonocytes, and a striking reduction in EspB expression and secretion. We conclude that S. boulardii maintained colonic epithelial barrier integrity and ameliorated inflammatory sequelae associated with C. rodentium infection by attenuating C. rodentium adherence to host epithelial cells through putative actions on the type III secretion system. Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10-/-) mice. Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA. Elevated mucosal IL-12/23p40 and IFN-gamma accompany early inflammation in IL-10-deficient (IL-10(-/-)) mice and then later decline while inflammation persists. This report addresses whether this cytokine profile reflects disease progression or inherent, age-related changes in mucosal immunity. IL-10(-/-) and wild-type (WT) mice were maintained in an ultrabarrier facility or transferred to conventional housing at 3, 12, or 30 weeks of age. Weight, stool changes, and histologic features were followed. Lamina propria mononuclear cells were cultured for cytokine analysis by ELISA. Ultrabarrier-housed IL-10(-/-) mice are statistically indistinguishable from WT mice by weight, disease activity index, and histologic inflammation. IL-10(-/-) mice but not WT, transferred at 3 weeks, develop colitis gradually, reaching a significant, sustained maximum by 15 weeks of age. Transfer at 12 weeks induces rapid disease onset in both strains, maximal at 15 weeks of age. Inflammation persists in IL-10(-/-), and WT recover. IL-10(-/-) and WT mice transferred at 30 weeks demonstrate transient diarrhea and weight loss but no chronic inflammation. Probiotics delay symptom onset only in the 12-week-old group. IFN-gamma production from ultrabarrier-housed IL-10(-/-) mice is elevated at 12 weeks of age, and older animals have decreased IFN-gamma and increased IL-4. IL-10 is important for suppressing inflammation after transfer at 3 weeks of age and limiting inflammation after transfer at 12 weeks but has little influence at 30 weeks of age. Colitis onset, progression, and response to probiotic therapy vary with immune system age, suggesting that a distinct, Th1-driven, age-dependent cytokine profile may contribute to increased colitis susceptibility in otherwise healthy mice. Effect of oral administration of Butyrivibrio fibrisolvens MDT-1 on experimental enterocolitis in mice. Department of Life Science, College of Agriculture, Meiji University, Higashimita, Tama-ku, Kawasaki 214-8571, Japan. Butyrivibrio fibrisolvens MDT-1, a butyrate-producing strain, was evaluated for use as a probiotic to prevent enterocolitis. Oral administration of the MDT-1 strain (10(9) CFU/dose) alleviated the symptoms of colitis (including body weight loss, diarrhea, bloody stool, organic disorder, and mucosal damage) that are induced in mice drinking water that contains 3.0% dextran sulfate sodium. In addition, myeloperoxidase (MPO) activity levels in colonic tissue were reduced, suggesting that MDT-1 mitigates bowel inflammation. The addition of MDT-1 culture supernatant inhibited the growth of nine clinical isolates of Campylobacter jejuni and Campylobacter coli that could potentially cause enterocolitis. Infection of mice with C. coli 11580-3, one of the isolates inhibited by MDT-1 in vitro, resulted in diarrhea, mucosal damage, increased MPO activity levels in colonic tissue, increased numbers of C. coli in the cecum, and decreased body weight gain. However, administration of MDT-1 to mice, prior to and during C. coli infection, reduced these effects. These results suggest that Campylobacter-induced enterocolitis can be alleviated by using B. fibrisolvens as a probiotic.
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