Kegg Pathway: Antidepressants

Actas Esp Psiquiatr. 2009 Jul; 37(4): 231-221
García-Portilla M

Depressive symptoms and disorders are highly prevalent throughout life, particularly in the middle-aged. From adolescence, women have a 1.5-3 times higher risk than men of suffering different depressive disorders. Traditionally, it has been assumed that transition to menopause, or perimenopause, is a period of higher depressive vulnerability, although there is some degree of controversy. This period seems to be associated with the appearance of both depressive symptoms and de novo depressive disorders, particularly if a background of depression exists. With regard to its etiopathogeny, genetic, hormonal, psychological and sociocultural factors have been suggested, but there are no solid data that support any of these explanations. Treatment basically depends on the severity of the disorder and includes Antidepressants and/or psychotherapy. Maintained treatment with hormone replacement therapy (estrogens) is under discussion. Key words: Depression. Perimenopause. Estrogens. Actas Esp Psiquiatr 2009;37(4):213-221.

Actas Esp Psiquiatr. 2009 Jul; 37(4): 205-212
Roncero C, Rodríguez-Urrutia A, Grau-López L, Casas M

The disorders classified as control of the impulses; explosive intermittent disorder, pathological gambling, kleptomania, pyromania, pathological gambling, hair pullers, compulsive purchases, skin picking and onychophagia are a heterogeneous set of clinical entities, most of them with little prevalence. Nevertheless, they cause important personal and social dysfunctions and present great comorbidity with other psychiatric disorders. Antipsychotics, antidepressive agents, serotoninergic agonists, naltrexone, beta blockers antiandrogen, lithium and anticonvulsants have been used in their pharmacological treatment. Currently, interest is growing on the use of the antiepileptics because their possible usefulness has been described in these disorders. However, the neurobiological effects are only partially known in some cases. We have reviewed the literature regarding the treatment of these disorders with mood stabilizers, (lithium, carbamazepine, valproate, phenitoin, oxcarbacepin, topiramate, lamotrigin, leviteracetam) and have described those studies on which the current knowledge and evidence are based. The results must be considered as provisional and must be updated in the future, since they are mostly based on case reports, case series or opened clinical trials, their being little knowledge based on double blind clinical trials. Key words:Impulse control disorders. Antiepileptic drug. Explosive intermittent disorder. Pathological gambling. Kleptomania. Pyromania. Hair pullers. Actas Esp Psiquiatr 2009;37(4):205-212.

Actas Esp Psiquiatr. 2009 Jul; 37(4): 191-195
Ramos J, Cordero A, Gutiérrez R, Zamarro M

Introduction. Psychiatrists use few symptoms when diagnosing depression. This study has aimed to know what symptoms are used by the psychiatrists to evaluate the severity of a depressive person compared to how they are evaluated when using a standardized instrument such as Hamilton's Rating Scale for Depression (HRSD-17). Methodology. A total of 100 depressed outpatients attended consecutively who met the ICD-10 criteria for depressive episode, dysthymia or adjustment disorders depressive types were studied. The depressed outpatients expressed their clinical situation on a Visual Analogue Scale (VAS) whose extreme values were the adjectives WELL and BAD. The psychiatrist evaluated them using a Clinical Global Impression (CGI) scale on the state of the patient's depressed mood, and Hamilton's Rating Scale for Depression (HRSD-17). The total scores obtained with those instruments and with the partial scores of the melancholic and anxious factors of the HRSD-17 were correlated (Pearson's R). Results. Psychiatrists give more importance to melancholic symptoms than to anxious ones to establish the severity of a depressed outpatient. Depressed outpatients give the same importance to their anxious and melancholic symptoms. In addition, the total score of the HRSD-17 is more influenced and shares a larger variance proportion with anxious symptoms than with melancholic ones. All the correlations calculated are statistically significant (p = 0.000). Conclusions. The authors discuss the influence that the HRSD-17 can have on seemingly precocious results offered by some clinical trials of Antidepressants drugs. Key words: Depression. Depressive symptoms. Measure. Evaluation. Hamilton scale. Actas Esp Psiquiatr 2009;37(4):191-195.

Drugs Today (Barc). 2009 Aug; 45(8): 599-608
Owen RT

Agomelatine is a melatonin analogue which represents a novel class of Antidepressants. It acts as an agonist at melatonin MT(1) and MT(2) receptors and as a specific antagonist at 5-HT(2C) receptors. It is rapidly absorbed orally and mainly metabolized via CYP1A2 hepatic isoenzymes, has no active metabolites and an elimination half-life of 1-2 hours. Short-term trials (6-8 weeks) have confirmed the compound's antidepressant effect in major depressive disorder at doses of 25-50 mg/day. It has comparable antidepressant activity to venlafaxine (75-150 mg/day) and in one trial, showed statistical superiority to sertraline 50-100 mg/day. In long-term studies agomelatine was superior to placebo for relapse prevention at 10 months and treatment adherence rates were higher than with venlafaxine and sertraline over 6 months. The drug has anxiolytic properties and a beneficial effect on sleep without affecting rapid eye movement (REM) activity. Although agomelatine is generally well tolerated with low adverse event discontinuation rates, it currently requires monitoring of liver function because a small number of patients had raised liver enzyme activities in the trial program. The compound has fewer effects on sexual function than venlafaxine and, unlike paroxetine, it causes minimal discontinuation symptoms upon abrupt withdrawal. Agomelatine is currently being investigated for other indications such as seasonal affective disorder, generalized anxiety disorder and bipolar depression.

BMJ. 2009; 339: b4229
Hippisley-Cox J, Coupland C

OBJECTIVE: To develop and validate two new fracture risk algorithms (QFractureScores) for estimating the individual risk of osteoporotic fracture or hip fracture over 10 years. DESIGN: Prospective open cohort study with routinely collected data from 357 general practices to develop the scores and from 178 practices to validate the scores. SETTING: General practices in England and Wales. PARTICIPANTS: 1 183 663 women and 1 174 232 men aged 30-85 in the derivation cohort, who contributed 7 898 208 and 8 049 306 person years of observation, respectively. There were 24 350 incident diagnoses of osteoporotic fracture in women and 7934 in men, and 9302 incident diagnoses of hip fracture in women and 5424 in men. MAIN OUTCOME MEASURES: First (incident) diagnosis of osteoporotic fracture (vertebral, distal radius, or hip) and incident hip fracture recorded in general practice records. RESULTS: Use of hormone replacement therapy (HRT), age, body mass index (BMI), smoking status, recorded alcohol use, parental history of osteoporosis, rheumatoid arthritis, cardiovascular disease, type 2 diabetes, asthma, tricyclic Antidepressants, corticosteroids, history of falls, menopausal symptoms, chronic liver disease, gastrointestinal malabsorption, and other endocrine disorders were significantly and independently associated with risk of osteoporotic fracture in women. Some variables were significantly associated with risk of osteoporotic fracture but not with risk of hip fracture. The predictors for men for osteoporotic and hip fracture were age, BMI, smoking status, recorded alcohol use, rheumatoid arthritis, cardiovascular disease, type 2 diabetes, asthma, tricyclic Antidepressants, corticosteroids, history of falls, and liver disease. The hip fracture algorithm had the best performance among men and women. It explained 63.94% of the variation in women and 63.19% of the variation in men. The D statistic values for discrimination were highest for hip fracture in women (2.73) and men (2.68) and were over twice the magnitude of the corresponding values for osteoporotic fracture. The ROC statistics for hip fracture were also high: 0.89 in women and 0.86 for men versus 0.79 and 0.69, respectively, for the osteoporotic fracture outcome. The algorithms were well calibrated with predicted risks closely matching observed risks. The QFractureScore for hip fracture also had good performance for discrimination and calibration compared with the FRAX (fracture risk assessment) algorithm. CONCLUSIONS: These new algorithms can predict risk of fracture in primary care populations in the UK without laboratory measurements and are therefore suitable for use in both clinical settings and for self assessment (www.qfracture.org). QFractureScores could be used to identify patients at high risk of fracture who might benefit from interventions to reduce their risk.

Curr Drug Targets. 2009 Nov 1; 10(11): 1052-1060
Bourin M, Chenu F, Hascoët M

Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with Antidepressants and mood stabilizers, a comparison of the activity of both Antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the Antidepressants (paroxetine, imipramine and desipramine) with the one of anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of anticonvulsants and Antidepressants is different, because veratrine limits the activity of anticonvulsants but not of Antidepressants. The anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to that induced by Antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant-like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as Antidepressants, but also as augmentation strategies for classical Antidepressants.

Anal Bioanal Chem. 2009 Nov 19;
Demeestere K, Petrović M, Gros M, Dewulf J, Van Langenhove H, Barceló D

This paper presents the development, optimization, and validation of an innovative method to analyze trace concentrations of seven selected psychoactive pharmaceuticals in environmental waters. Hereby, the solid-phase extraction (SPE) potential of molecularly imprinted polymers (MIPs) in terms of extraction recovery, breakthrough, precision, and selectivity is studied for the first time. Instrumental analysis by ultra-performance liquid chromatography coupled to triple quadrupole mass spectrometry allowed a rapid (run time = 7.5 min) and sensitive (instrumental detection limit /= 3). Compared to the widely used hydrophilic-lipophilic balanced (HLB) polymers, the newly developed MIPs indicated to be more resistant toward matrix effects induced ion signal suppression particularly when dealing with relative dirty samples like STP influents. As a result of the better selectivity, the MDL obtained with the MIP-based SPE method was up to a factor of 7 lower compared to those obtained with a recently reported multi-residue HLB method. However, optimizing a HLB method in terms of selectivity, e.g., by introducing a stronger washing protocol, can significantly reduce its MDL up to values approximating those obtained with MIPs.

Neuropsychopharmacology. 2009 Nov 18;
Carr GV, Bangasser DA, Bethea T, Young M, Valentino RJ, Lucki I

The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel Antidepressants.Neuropsychopharmacology advance online publication, 18 November 2009; doi:10.1038/npp.2009.183.

Neuropsychopharmacology. 2009 Nov 18;
Perisic T, Zimmermann N, Kirmeier T, Asmus M, Tuorto F, Uhr M, Holsboer F, Rein T, Zschocke J

Aberrant biochemical processes in the brain frequently go along with subtle shifts of the cellular epigenetic profile that might support the pathogenic progression of psychiatric disorders. Although recent reports have implied the ability of certain Antidepressants and mood stabilizers to modulate epigenetic parameters, studies comparing the actions of these compounds under the same conditions are lacking. In this study, we screened amitriptyline (AMI), venlafaxine, citalopram, as well as valproic acid (VPA), carbamazepine, and lamotrigine for their potential actions on global and local epigenetic modifications in rat primary astrocytes. Among all drugs, VPA exposure evoked the strongest global chromatin modifications, including histone H3/H4 hyperacetylation, 2MeH3K9 hypomethylation, and DNA demethylation, as determined by western blot and luminometric methylation analysis, respectively. CpG demethylation occurred independently of DNA methyltransferase (DNMT) suppression. Strikingly, AMI also induced slight cytosine demethylation, paralleled by the reduction in DNMT enzymatic activity, without affecting the global histone acetylation status. Locally, VPA-induced chromatin modifications were reflected at the glutamate transporter (GLT-1) promoter as shown by bisulfite sequencing and acetylated histone H4 chromatin immunoprecipitation analysis. Distinct CpG sites in the distal part of the GLT-1 promoter were demethylated and enriched in acetylated histone H4 in response to VPA. For the first time, we could show that these changes were associated with an enhanced transcription of this astrocyte-specific gene. In contrast, AMI failed to stimulate GLT-1 transcription and to alter promoter methylation levels. In conclusion, VPA and AMI globally exerted chromatin-modulating activities using different mechanisms that divergently precipitated at an astroglial gene locus.Neuropsychopharmacology advance online publication, 18 November 2009; doi:10.1038/npp.2009.188.

Cell Signal. 2009 Nov 13;
Mnie-Filali O, Amraei MG, Benmbarek S, Archer-Lahlou E, Peñas-Cazorla R, Vilaró MT, Boye SM, Piñeyro G

Serotonin 4 receptors (5-HT4Rs) are particularly abundant within the limbic system, where they constitute potential targets for the development of novel, rapid acting Antidepressants. However, the population of limbic 5-HT4Rs is not homogenous, comprising various isoforms of which 5-HT4(a) and 5-HT4(b) are among the most abundant variants. Sequence divergence at their C-termini is predictive of specificity in isoform signalling and regulation, but the differences, if any, remain ill-defined. The present study compared isoforms 5-HT4(a) and 5-HT4(b) in their ability to undergo endocytic regulation following exposure to 5-HT and to the putatively fast acting antidepressant RS67333. Both ligands differed in their ability to induce internalization of either isoform, 5-HT being more effective than RS67333 in HEK293 cells and in neurons. In contrast, trafficking induced by 5-HT was isoform-specific. In particular, while PKC, GRK2 and betaarrestin were necessary for 5-HT4(a)R internalization, sequestration of 5-HT4(b)Rs required PKC but not GRK2 and relied significantly less on betaarrestin. After endocytosis, isoform (b) appeared scattered throughout the intracellular compartment and efficiently recycled to the membrane upon agonist removal. Isoform (a) accumulated in the perinuclear compartment and displayed little recycling. Isoform-specific subcellular distribution was present in HEK293 cells and in neurons. In neurons, where internalization by RS67333 was more pronounced than in HEK293 cells, receptors internalized by this ligand followed the same distribution pattern as observed with 5-HT. These results point to isoform-related differences in the way that 5-HTRs respond to different ligands. Such diversity should be taken into account when developing therapeutic agents that target 5-HT4Rs.

Addiction. 2009 Dec; 104(12): 2110-2117
Van Schayck CP, Kaper J, Wagena EJ, Wouters EF, Severens JL

Objectives In healthy smokers, Antidepressants can double the odds of cessation. Because of its four times lower costs and comparable efficacy in healthy smokers, nortriptyline appears to be favourable compared to bupropion. We assessed which of both drugs was most effective and cost-effective in stopping smoking after 1 year compared with placebo among smokers at risk or with existing chronic obstructive pulmonary disease (COPD). Methods A total of 255 participants, aged 30-70 years, received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for 12 weeks. Prolonged abstinence from smoking was defined as a participant's report of no cigarettes from week 4 to week 52, validated by urinary cotinine. Costs were calculated using a societal perspective and uncertainty was assessed using the bootstrap method. Results The prolonged abstinence rate was 20.9% with bupropion, 20.0% with nortriptyline and 13.5% with placebo. The differences between bupropion and placebo [relative risk (RR) = 1.6; 95% confidence interval (CI) 0.8-3.0] and between nortriptyline and placebo (RR = 1.5; 95% CI 0.8-2.9) were not significant. Severity of airway obstruction did not influence abstinence significantly. Societal costs were euro1368 (2.5th-97.5th percentile 193-5260) with bupropion, euro1906 (2.5th-97.5th 120-17 761) with nortriptyline and euro1212 (2.5th-97.5th 96-6602) with placebo. Were society willing to pay more than euro2000 for a quitter, bupropion was most likely to be cost-effective. Conclusions Bupropion and nortriptyline seem to be equally effective, but bupropion appears to be more cost-effective when compared to placebo and nortriptyline. This impression holds using only health care costs. As the cost-effectiveness analyses concern some uncertainties, the results should be interpreted with care and future studies are needed to replicate the findings.

World J Biol Psychiatry. 2009; 10(4): 302-312
Naderi-Heiden A, Shadnia S, Salimi AR, Naderi A, Naderi MM, Schmid D, Gleiss A, Kasper S, Frey R

In a prospective hospital-based cohort study, we addressed the question of severity and outcome of antidepressant poisonings in patients who attended the Loghman-Hakim Hospital Poison Center, the only national center in Tehran dedicated for detoxification. The aim of the study was to find out if tricyclic antidepressant (TCA) intoxications require more therapeutic efforts than selective serotonin reuptake inhibitor (SSRI) intoxications. The study was applied over a 7-week period (28 March-20 May 2006). From 3578 intoxications, 334 patients with antidepressant or lithium self-poisoning were identified (9.3% of all poisoning cases; 233 females, 101 males; median age 24 years, min 13, max 70). Compared to SSRI single-substance intoxications (n=17), TCA single-substance intoxications (n=73) were associated with: (1) a significantly lower level of consciousness (P=0.005); (2) a significantly higher admission frequency (80.8 vs. 35.3%; P<0.001); and (3) a higher intubation frequency (13.7 vs. 0%; P=ns). SSRI multiple-substance intoxications were associated with a significantly lower level of consciousness than SSRI single-substance intoxications (P=0.042), while there was no significant difference between TCA multiple- and single-substance intoxications. This study suggests that an overdose with SSRIs results in a more favourable clinical outcome than an overdose with TCAs.

World J Biol Psychiatry. 2009; 10(4): 295-301
Grønli O, Stensland GO, Wynn R, Olstad R

We examined changes in serum levels of a selection of neurotrophic factors, TSH, HGH and cortisol in conjunction with ECT treatment. Fifteen patients suffering from affective disorders were included, all were treated with Antidepressants and psychotherapy and 10 also with ECT. The patients were examined clinically and with blood samples during treatment. Serum levels of cortisol, thyroid stimulating hormone (TSH), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neuropetide Y (NPY) and human growth hormone (HGH) were studied. No significant changes were found in levels of NGF, BDNF, NT3, HGH and TSH. A change in NPY levels was statistically significant, but of uncertain clinical value as it affected only two patients. Levels of cortisol rose significantly during treatment. We did find significant correlations between the base values of NGF and HAM-D scores at inclusion and between the end-values of NT3 and NPY and the HAM-D scores prior to discharge. We were unable to reproduce findings from animal studies suggesting that a range of neurotrophic factors rise during ECT treatment. This may be because of physiological differences between animals and humans or, possibly, a result of the small number of patients included in this pilot study.

World J Biol Psychiatry. 2009; 10(4): 269-275
Mendlewicz J

Depression is increasingly prevalent in Western countries. It has severe consequences and is associated with increased rates of disability, morbidity, and mortality. Despite numerous therapeutic options, a great number of depressed patients do not achieve full remission. In addition, despite good short-term outcomes, long-term therapeutic results remain disappointing and associated with a poor prognosis, raising significant concern in terms of public health. Impaired sleep - especially insomnia - may be at least partly responsible for this problem. Very close relationships between major depressive disorder (MDD) and sleep disorders have been observed. In particular, residual symptoms of sleep disturbance in a remitted patient may predict a relapse of the disease. However, most currently available Antidepressants do not always take into consideration the sleep disturbances of depressed patients; some agents long used in clinical practice even appear to worsen them by their sleep-inhibiting properties. But some other new medications were shown to relieve early sleep disturbance in addition to alleviating other depression-related symptoms. This positive impact should promote compliance with medication and psychological treatments, and increase daytime performance and overall functioning. Complete remission of MDD appears therefore to depend on the relief of sleep disturbances, a core symptom of MDD that should be taken into consideration and treated early in depressed patients.

Reg Anesth Pain Med. 2009 September/October; 34(5): 514-521
Benzon HT, Chekka K, Darnule A, Chung B, Wille O, Malik K

OBJECTIVE:: A patient with postherpetic neuralgia (PHN) did not respond to medications, either singly or in combination, or to intrathecal methylprednisolone but responded to intrathecal alcohol. This evidenced-based case management article evaluates and grades the evidence for the prevention and treatment of PHN. METHODS:: A search of published English-language studies on the prevention and treatment of PHN was made. RESULTS:: Randomized clinical studies showed the efficacy of antiviral agents in the prevention of PHN and the use of anticonvulsants, Antidepressants, opioids, and Lidoderm patch in the treatment of PHN (level A evidence). The role of epidural local anesthetic and steroid injections in preventing PHN has not been completely established (level B evidence). Intrathecal steroid injections and topical capsaicin may be effective in PHN (level B evidence). No randomized controlled study supports the usefulness of spinal cord stimulation and intrathecal alcohol. CONCLUSIONS:: Postherpetic neuralgia should be managed pharmacologically. If not effective, intrathecal steroid injections or nerve blocks may be tried. Spinal cord stimulation or intrathecal alcohol should be used only as a last resort.

Circ Heart Fail. 2009 Nov 1; 2(6): 582-590
Fosbøl EL, Gislason GH, Poulsen HE, Hansen ML, Folke F, Schramm TK, Olesen JB, Bretler DM, Abildstrøm SZ, Sørensen R, Hvelplund A, Køber L, Torp-Pedersen C

BACKGROUND: Depression worsens the prognosis in patients with cardiac disease, and treatment with Antidepressants may improve survival. Guidelines recommend use of selective serotonin reuptake inhibitors (SSRIs), but knowledge of the prognostic effect of different classes of Antidepressants is sparse. METHODS AND RESULTS: We studied 99 335 patients surviving first hospitalization for heart failure (HF) from 1997 to 2005. Use of HF medication and Antidepressants (divided into tricyclic Antidepressants [TCA] and SSRI) was determined by prescription claims. Risk of overall and cardiovascular death associated with Antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due to cardiovascular causes (median follow-up, 1.9 years; 5, 95% fractiles, 0.04 to 7.06 years). Use of beta-blockers was associated with decreased risk of cardiovascular death (hazard ratio [HR], 0.77; 95% CI, 0.75 to 0.79). Antidepressants were prescribed to 19 411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and beta-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of beta-blockers and TCA (P for interaction <0.01). CONCLUSIONS: Use of Antidepressants in patients with HF was associated with worse prognosis. Coadministration of SSRIs and beta-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and beta-blockers. To further clarify this, clinical trials testing the optimal antidepressant strategy in patients with HF are warranted.

Anasthesiol Intensivmed Notfallmed Schmerzther. 2009 Nov; 44(11-12): 736-44
Wörner J, Rukwied R, Konrad C

The sensation of pain arises through stimulation of peripheral nociceptors and is transmitted centrally involving several receptors and ion channels. In addition many endogenous physiologic pain-modulating mechanisms exist. Besides of classical analgesics, numerous other drugs showed analgesic properties based on diverse modes of actions along the pain pathway. These co-analgesics, administered in combination with classical drugs, are able to reduce painful states of different origin. We describe the peripheral action sites of co-analgesics, such as cannabinoids, capsaicin, bisphosphonates, steroids and somatostatin. We also summarise the effect of peripherally and centrally acting ion-channel blockers, e.g. local anaesthetics, carbamazepine and tolperisone working on sodium channels and gabapentin and pregabalin working on calcium channels. Finally, central analgesic mechanisms are discussed, for instance the inhibition of NMDA-receptors by ketamine or magnesium, the stimulation of alpha2-receptors by clonidine, tizanidine or Antidepressants, the activation of GABA-receptors through baclofen and other analgesic mechanisms of i.e. ondansetron and neostigmine.

Arq Gastroenterol. 2009 Jul-Sep; 46(3): 233-40
Domingues GR, Moraes-Filho JP

CONTEXT: Non-cardiac chest pain or functional chest pain is a syndrome with high prevalence in occidental world. Findings on 15%-30% of coronary angiograms performed in patients with chest pain are normal. Causes significant impact in quality of life of patients and is associated with increased use of the health care facilities. DATA SOURCES: To this review the following data base were accessed: Medline, the Cochrane Library, LILACS. The limit was the last 5 years publications and were selected relevant original articles, reviews, consensus, guidelines and meta-analysis. RESULTS: Forty-four papers were selected, 28 original articles, 12 reviews, 2 guidelines, 1 consensus and 1 meta-analysis. CONCLUSIONS: Exclusion of cardiac disease is of crucial importance. On the other hand non-cardiac chest pain could be related to gastrointestinal, muscular and respiratory causes and/or psychological disturbances. Treatment aims to attack mechanism generator in order to relieve or to eliminate symptoms. Drugs are the cornerstone of treatment, exception to achalasia patients because those have better response to dilation of the esophagus or surgery, and to those who need intensive psychological therapy. The most important drugs used are proton pump inhibitors and tricyclic Antidepressants, the latter, to modulate central signal process (visceral hypersensitivity) and autonomic response. Recently, new diagnostic facilities, and also therapeutic modalities, such as esophageal botulin toxin injection and hypnosis are under investigations. In the near future, maybe some of them would take a place in the therapeutic scenario of these patients.

Neuropharmacology. 2009 Nov 13;
Hou Y, Aboukhatwa MA, Lei DL, Manaye K, Khan I, Luo Y

Increasing evidence suggests that depression may be both a cause and consequence of neurological disorders such as Alzheimer's disease (AD), and that Antidepressants could provide an alternative strategy to current AD therapies.Association of side effect and herbal-drug interaction with conventional antidepressant and St. John's wort warrant investigating new antidepressant drugs. Antidepressant effects of ginkgo biloba extract (EGb 761) have been demonstrated in animal models of depression and in human volunteers. We report here that ginkgo flavonols quercetin and kaempferol stimulates depression-related signaling pathways involving brain-derived neurotrophic factor BDNF/phosphorylation of cyclic AMP response element binding protein CREB/postsynaptic density proteins PSD95, and reduces amyloid-beta peptide (Abeta) in neurons isolated from double transgenic AD mouse (TgAPPswe/PS1e9). In addition, enhanced BDNF expression and reduction of Abeta oligomers was confirmed in hippocampus of the double transgenic mice administered with flavonol, which correlates with cognitive improvement behaviors in these mice. The present results suggest that stimulating BDNF and reducing Abeta toxicity by natural flavonols provide a therapeutic implication for treatment of AD.

Br J Clin Pharmacol. 2009 Nov; 68(5): 743-51
Jolly K, Gammage MD, Cheng KK, Bradburn P, Banting MV, Langman MJ

AIMS: To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs. METHODS: Case-control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care. RESULTS: Noncardiac drug risk was posed by antipsychotics and Antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic Antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively. CONCLUSIONS: Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic Antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.