Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro.

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1­adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D­ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D­AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.

Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To investigate the efficacy and safety of antidepressants for back and osteoarthritis pain compared with placebo. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to 15 November and updated on 12 May 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials comparing the efficacy or safety, or both of any antidepressant drug with placebo (active or inert) in participants with low back or neck pain, sciatica, or hip or knee osteoarthritis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data. Pain and disability were primary outcomes. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst pain or disability). A random effects model was used to calculate weighted mean differences and 95% confidence intervals. Safety (any adverse event, serious adverse events, and proportion of participants who withdrew from trials owing to adverse events) was a secondary outcome. Risk of bias was assessed with the Cochrane Collaboration's tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework. RESULTS: 33 trials (5318 participants) were included. Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference -5.30, 95% confidence interval -7.31 to -3.30) at 3-13 weeks and low certainty evidence that SNRIs reduced osteoarthritis pain (-9.72, -12.75 to -6.69) at 3-13 weeks. Very low certainty evidence showed that SNRIs reduced sciatica at two weeks or less (-18.60, -31.87 to -5.33) but not at 3-13 weeks (-17.50, -42.90 to 7.89). Low to very low certainty evidence showed that tricyclic antidepressants (TCAs) did not reduce sciatica at two weeks or less (-7.55, -18.25 to 3.15) but did at 3-13 weeks (-15.95, -31.52 to -0.39) and 3-12 months (-27.0, -36.11 to -17.89). Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (-3.55, -5.22 to -1.88) and disability due to osteoarthritis at two weeks or less (-5.10, -7.31 to -2.89), with low certainty evidence at 3-13 weeks (-6.07, -8.13 to -4.02). TCAs and other antidepressants did not reduce pain or disability from back pain. CONCLUSION: Moderate certainty evidence shows that the effect of SNRIs on pain and disability scores is small and not clinically important for back pain, but a clinically important effect cannot be excluded for osteoarthritis. TCAs and SNRIs might be effective for sciatica, but the certainty of evidence ranged from low to very low. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020158521.

Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 9: Interactions Mediated by Drug-metabolizing Cytochrome P450 Enzymes.

This column is the ninth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmaco-dynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. The seventh and eighth columns presented the concept of relative receptor binding and included tables summarizing the relative receptor binding affinity of currently available antipsychotics and antidepressants, respectively. This ninth and final column in this series discusses pharmacokinetic DDIs with a focus on psychiatric medications and contains 3 tables. The first table is an abbreviated version of a table available online showing which drugs are substrates for which cytochrome P450 (CYP) enzymes and which drugs are inhibitors or inducers of specific CYP enzymes. The abbreviated version of the table presented in this column focuses on psychiatric medications. This table and the larger website version can allow prescribers to anticipate which drug combinations may pose the risk of a CYP enzyme-mediated DDI. The second table summarizes which antidepressants inhibit specific CYP enzymes and which antidepressants do not or are unlikely to inhibit specific CYP enzymes. The third table presents psychiatric medications whose clearance is not principally dependent on CYP enzyme-mediated oxidative metabolism as a necessary step in their clearance from the body. The latter 2 tables inform prescribers as to which drugs they may prefer to use to avoid CYP enzyme-mediated DDIs. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 8: Relative Receptor Binding Affinity as a Way of Understanding the Differential Pharmacology of Currently Available Antidepressants.

This column is the eighth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. That column focused particularly on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors and also DDIs involving psychiatric medications with adverse effects on the cardiovascular system and on the central nervous system. The seventh column presented the concept of relative receptor binding and included a table summarizing the relative receptor binding affinity of antipsychotics including all of the newer agents as well as some of the older agents such as haloperidol. This eighth column in this series presents a parallel table to the one in the seventh column summarizing the relative receptor binding affinity of currently available antidepressants. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

Prevalence, incidence, indication, and choice of antidepressants in patients with and without chronic kidney disease: a matched cohort study in UK Clinical Practice Research Datalink.

PURPOSE: People with chronic kidney disease (CKD) have an increased prevalence of depression, anxiety, and neuropathic pain. We examined prevalence, incidence, indication for, and choice of antidepressants among patients with and without CKD. METHODS: Using the UK Clinical Practice Research Datalink, we identified patients with CKD (two measurements of estimated glomerular filtration rate < 60 mL/min/1.73m2 for ≥3 months) between April 2004 and March 2014. We compared those with CKD to a general population cohort without CKD (matched on age, sex, general practice, and calendar time [index date]). We identified any antidepressant prescribing in the six months prior to index date (prevalence), the first prescription after index date among non-prevalent users (incidence), and recorded diagnoses (indication). We compared antidepressant choice between patients with and without CKD among patients with a diagnosis of depression. RESULTS: There were 242 349 matched patients (median age 76 [interquartile range 70-82], male 39.3%) with and without CKD. Prevalence of antidepressant prescribing was 16.3 and 11.9%, and incidence was 57.2 and 42.4/1000 person-years, in patients with and without CKD, respectively. After adjusting for confounders, CKD remained associated with higher prevalence and incidence of antidepressant prescription. Regardless of CKD status, selective serotonin reuptake inhibitors were predominantly prescribed for depression or anxiety, while tricyclic antidepressants were prescribed for neuropathic pain or other reasons. Antidepressant choice was similar in depressed patients with and without CKD. CONCLUSIONS: The rate of antidepressant prescribing was nearly one and a half times higher among people with CKD than in the general population. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Modulatory Effects of Antidepressant Classes on the Innate and Adaptive Immune System in Depression.

Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies - in clinical and pre-clinical populations.

[Austrian expenditures on psychopharmaceutical drugs between 2006 and 2013]. / Analyse der Ausgaben für Psychopharmaka in Österreich von 2006 bis 2013.

OBJECTIVES: Health costs, which are increasing at a yearly rate of 4 %, represent 11% and thus a large share of Austria's gross domestic product (GDP). High expenditures derive frommental health care costs, including medication. In this article we investigate whether the costs and usage of psychopharmaceutic products in Austria are rising. METHOD: We did a descriptive analysis of the sales figures and number for packaging units of pharmaceutical products of ATC-classes N05 and N06 in all Austrian hospitals, pharmacies and medicine chests for the years 2006-2013. All data were provided free of charge by IMSHealth. RESULTS: The sales volume and number of prescribed packaging units of pharmaceuticals of ATC-classes N05 and N06 increased over the time period in question. In 2013, about 25% more packaging units were being sold than in 2006. Among the two ATC-classes, however, the indication subgroups developed differently. Expenditures increased a total of about 31%within the period of consideration. CONCLUSIONS: The increase in psycho-pharmaceutical sales exceeds the expansion rates of other health expenditures (17.8 %). During the 9 years of observation, 25% more psychopharmaceutical products were sold. This may result from increased prevalence of mental disorders, higher usage or an increment in prescriptions.

Efficacy and acceptability of antidepressants on the continuum of depressive experiences in patients with cancer: Systematic review and meta-analysis.

BACKGROUND: Patients with cancer are particularly vulnerable to depressive experiences, ranging from severe emotional reactions to proper depressive syndromes, including major depression. These experiences may deeply affect the course and outcome of the disease. The aim of this study was to assess the efficacy acceptability of antidepressants on the continuum of depressive experiences in patients suffering from cancer. METHODS: MEDLINE, EMBASE, PsycINFO, CENTRAL, as well as websites of regulatory agencies, clinical trial repositories and pharmaceutical companies, were systematically searched for published and unpublished randomised trials assessing the efficacy of antidepressants versus placebo in patients with cancer. Efficacy of antidepressants at the end of the study was the primary outcome. The review protocol was registered with PROSPERO (CRD42014013440). RESULTS: A total of 19 studies contributed to the analysis. Antidepressants (particularly the selective serotonin-reuptake inhibitors and mianserin) were more effective than placebo in relieving depressive experiences in both patients with major depression or depressive symptoms (standardised mean difference -0.596, 95% confidence interval -1.041 to -0.150), as well as in patients with other cancer-related distressing symptoms (standardised mean difference -0.229, 95% confidence interval -0.419 to -0.039). We found evidence that efficacy was positively associated with length of treatment. No differences between antidepressants and placebo were found in terms of overall acceptability. CONCLUSIONS: Antidepressants should be considered as one treatment option for relieving the burden of depressive experiences in patients with cancer.

Depression during Pregnancy.

A proportion of women enter pregnancy with active psychiatric symptoms or disorders, with or without concomitant psychotropic medication. Studies report that exposure to untreated depression and stress during pregnancy may have negative consequences for birth outcome and child development. Studies also report that antenatal exposure to antidepressant medications may have adverse consequences for birth outcome and child development. Antidepressant medication use during pregnancy leads to a small increased risk of miscarriage, a possible small increased risk of congenital cardiac malformations, a small increased risk of preterm birth, a small increased risk of persistent pulmonary hypertension of the newborn (PPHN), and transient neonatal symptoms in up to one-third of neonates. In addition, there is a possible increased risk of delayed motor development in children. Several recent systematic reviews and meta-analyses of the existent literature emphasize that there are minimal definitive conclusions to guide treatment recommendations. This review describes best practices for the management of depression in pregnancy, and it provides suggestions for future research.

[Antidepressants in epilepsy]. / Antidepresivos en epilepsia.

Depression is a common condition in patients with epilepsy that entails a deterioration of the quality of life of this population and that, therefore, requires appropriate treatment. The potential risk of antidepressants in relation to the seizure threshold is overestimated by many professionals, and this has an influence when it comes to making the decision to treat them. It sometimes means that the patients do not receive antidepressant drugs. In this regard, the aim of this review is to present the current state of the art in terms of the safety of antidepressants in patients with epilepsy. A search of the medical literature was conducted and, following its analysis, the most significant results are presented. Current information indicates that most antidepressants are safe for epileptic patients at therapeutic doses and that the risk of seizures occurs mainly in cases of overdose. Preferred drugs for treating depression in epilepsy are serotonin reuptake inhibitors. Bupropion and tricyclic antidepressants must be avoided.

TITLE: Antidepresivos en epilepsia.La depresion es una entidad frecuente en pacientes con epilepsia que comporta un deterioro de la calidad de vida de esta poblacion y que, por tanto, requiere un tratamiento adecuado. El riesgo potencial de los antidepresivos en relacion con el umbral convulsivo esta sobrevalorado por parte de muchos profesionales, lo que influye en la decision de tratarlos y, en ocasiones, priva a los pacientes de recibir farmacos antidepresivos. En ese sentido, la presente revision tiene por objetivo presentar el estado actual del conocimiento en relacion con la seguridad de los antidepresivos en pacientes con epilepsia. Se realizo una busqueda de la literatura medica y, tras su analisis, se presentan los resultados mas relevantes. La informacion actual indica que la mayoria de antidepresivos son seguros en dosis terapeuticas para pacientes con epilepsia, y que el riesgo de crisis ocurre, principalmente, en casos de sobredosis. Los farmacos de eleccion para tratar la depresion en epilepsia son los inhibidores de recaptacion de serotonina. Deben evitarse el bupropion y los antidepresivos triciclicos.

Maprotiline treatment differentially influences cardiac β -adrenoreceptors expression under normal and stress conditions

Alterations in cardiac function were observed in antidepressants treated patients and published in several clinical reports. These detected changes could be either a consequence of the treatment or of depression itself, which has already been proved to be a risk factor in heart diseases. In order to determine a possible influence of chronic treatment with norepinephrinergic reuptake inhibitor, maprotiline, on the heart, we investigated gene expression of cardiac β-adrenoceptors both in controls and in animals with signs of depression. The rats were divided into two groups, unstressed controls and those exposed to chronic unpredictable mild stress (CUMS). The groups were further divided into two subgroups, one receiving daily intraperitoneal injections of vehicle (sterile water) and another one maprotiline (10 mg/kg) for four weeks. Tissue samples were collected after the last application. Gene expression of cardiac β1- and β2-adrenoceptor was determined using Real-time RT-PCR analysis. Our results show that in control animals expression of both adrenoreceptors was decreased in the right atria after 4 weeks of maprotiline application. Contrary, the same treatment led to a significant increase in expression of cardiac β1-adrenoceptor in the stressed rats, with no change in the characteristics of β2-adrenoceptor. Our findings might reflect the that molecular mechanisms are underlying factors involved in the development of cardiovascular diseases linked with antidepressant treatment.

Vários relatórios clínicos observaram alterações de funcionamento cardíaco de pacientes depressivos que foram tratados com os antidepressivos. As alterações detectadas podem ser consequência do tratamento ou, por outro lado, da depressão que, como se tem provado, é um fator de risco no caso de doenças cardíacas. De modo a determinar a possível influência de tratamento crônico com o inibidor da recaptação de norepinefrina, maprotilina, no coração, foi investigada a expressão do gene aos receptores β-adrenérgicos cardíacos dos animais em grupos de controle e em grupos com sinais de depressão. Os ratos foram divididos em grupos de controle não estressados e os grupos de ratos submetidos ao estresse crônico moderado imprevisível (CUMS). Os grupos foram, ainda, divididos em dois subgrupos, que, durante quatro semanas, diariamente receberam injeções intraperitoneais de placebo (água estéril) ou de maprotilina (10 mg/kg). As amostras de tecido foram coletadas após a última aplicação. A expressão do gene aos receptores adrenérgicos β1 e β2 foi determinada utilizando a análise PCR quantitativa em tempo real (RT-PCR). Os nossos resultados demonstram a diminuição de expressão dos ambos os receptores adrenérgicos no átrio direito dos animais do grupo de controle depois de quatro semanas de aplicação de maprotilina. Em contraste, o mesmo tratamento conduziu ao aumento significativo na expressão do receptor β1-adrenérgico no coração dos ratos estressados, sem qualquer alteração nas características do receptor β2-adrenérgico. Estes resultados podem refletir os mecanismos moleculares envolvidos no desenvolvimento de doenças cardiovasculares associadas ao tratamento com os antidepressivos.

Use of antidepressants in the treatment of chronic pain.

There is a high prevalence of chronic pain disorders in the population and the individual and societal costs are large. Antidepressants have been used in the treatment of chronic pain and the pain-relieving effects are independent of the mood-elevating properties. We reviewed randomised-controlled trials, systematic reviews and meta-analyses of antidepressants in the treatment of chronic pain disorders which were identified through searches of MEDLINE and EMBASE. Antidepressants have proved to be effective in the treatment of fibromyalgia, chronic low back pain, diabetic neuropathy, postherpetic neuralgia and chronic headache, in particular tricyclic antidepressants (TCAs). There is emerging evidence that newer dual-action antidepressants are equally efficacious. Antidepressants provide a viable option in the management of chronic pain disorders. Further research into novel antidepressants will aid the pain clinician in optimising treatment for patients.

Birth outcomes following prenatal exposure to antidepressants.

BACKGROUND: Antidepressant use during pregnancy and the peripartum period is common despite the absence of clear evidence-based guidelines to direct clinical use of these compounds. METHOD: We compared obstetrical and neonatal outcomes as recorded in medical records among 84 pregnant women with major depressive or anxiety disorders (DSM-IV criteria) who took antidepressants during pregnancy (cases) versus a 2:1 age- and parity-matched control group of 168 unexposed women. Women in the case group had sought psychiatric consultation regarding the use of medication from the Perinatal and Reproductive Psychiatry Program at the Massachusetts General Hospital between 1996 and 2000. RESULTS: There were no significant differences among cases versus controls and their offspring, with respect to various neonatal and obstetrical outcomes, including gestational age and weight, although 1-minute Apgar scores were slightly lower in exposed infants. Admissions to the special care nursery were more frequent, but briefer and based on relatively minor indications, among case newborns. There were no significant differences in neonatal outcomes between exposures to serotonin reuptake inhibitor (SRI) and tricyclic (TCA) antidepressants. CONCLUSION: This retrospective cohort study found no evidence of major increases in risk of adverse obstetrical or neonatal outcomes following prenatal exposure to antidepressants, nor between SRIs and TCAs. Larger, prospective studies with specific neurobehavioral measures are required to resolve current uncertainties about safe and effective use of antidepressants by pregnant women.

Differential effects of classical and atypical antipsychotic drugs on rotenone-induced neurotoxicity in PC12 cells.

Although classical and atypical antipsychotics may have different effects against neurotoxicity, the underlying mechanisms remain to be elucidated. In the present study, we compared the atypical agents, risperidone (RIP), olanzapine (OLZ), and quetiapine (QTP), with the classical agent haloperidol (HAL) in reducing cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor, in PC12 cells. We also determined whether there were differential effects of RIP and HAL on the expression of brain-derived neurotrophic factor (BDNF), signal transducers and activators of transcription-3 (STAT-3), and the immediate early gene c-fos, as well as intracellular levels of calcium. Exposure to 6 muM rotenone for 24 h resulted in a significant decrease in cell viability and apoptotic alteration. The rotenone-induced cytotoxicity was dose-dependently worsened by pretreatment with HAL, but significantly improved by the aforementioned atypical agents at low doses. Real-time PCR analysis revealed that HAL pretreatment significantly increased BDNF mRNA expression but did not alter c-fos and STAT-3 expression compared to rotenone-exposed cells. Unlike HAL, RIP pretreatment produced a significant elevation of all the three substance mRNA expression and the expression intensity was 2.6- to 4.6-fold greater than HAL. Pretreatment with RIP, but not HAL, also effectively prevented an elevation of intracellular levels of calcium provoked by rotenone. These results suggest that the protective effects of atypical antipsychotics are associated with a greater capacity to enhance pro-cell survival factors, therapeutic biomarker expression, and blockade of calcium influx. This may provide an alternative for explaining therapeutic advantages of atypical agents observed in clinical use.

Association between antidepressant use and prescribing of gastric acid suppressants.

OBJECTIVE: To determine whether an increased risk of gastrointestinal events is present in younger, generally healthy adults who consume antidepressants. METHOD: We performed a retrospective cohort study using the pharmacy records of Canadian Forces (CF) members who received antidepressants between June 1997 and November 2002, excluding those taking bupropion for smoking cessation. The control cohort comprised members who received salbutamol. Changes in use of gastric acid-reducing agents (GARs) and incident GAR prescribing rates were compared pre- and postinitiation of target medications. We performed ogistic regression analyses to evaluate the effects of age, sex, and concomitant medication use on GAR prescribing. RESULTS: A total of 8722 antidepressant exposures were identified among 5588 CF members. The control cohort consisted of 3059 people with 4154 salbutamol exposures. The number of incident GAR prescriptions decreased in both groups postexposure; however, the rate of decrease was significantly greater among salbutamol users (odds ratio 1.38; 95%CI, 1.12 to 1.71). Antidepressant users were significantly more likely to receive a new prescription for GAR following both short-term and long-term exposure (adjusted odds ratio 4.93; 95%CI, 2.66 to 9.21 and 2.83; 95%CI, 2.05 to 3.92, respectively). Antiplatelet agents, bisphosphonates, oral corticosteroids, and nonsteroidal antiinflammatory drugs were significant predictors of GAR prescription. CONCLUSION: Consistent with other reports, this study has identified that antidepressant use increases the risk for use of a gastric acid suppressant. Careful consideration should thus be made with regard to increased gastric event risk among antidepressant users.

Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.

Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be "prevented" or "cured". In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, "specificity" of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, "multi-target" agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to "network theory" analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.

Bipolar depression: an overview.

Depressive episodes are significant in bipolar illness since patients can spend up to one-third of their lives in depression. Although the treatment of bipolar depression remains an understudied area, new data from randomized, controlled trials and naturalistic studies have expanded the range of treatments available. The main aim in the treatment of bipolar depression is the prevention of the patient switching to mania and cycle acceleration, and antidepressant therapy may be contraindicated because of the risk for switching. Guidelines for the acute treatment of bipolar depression emphasize treatment with a mood stabilizer, of which lithium has been the most thoroughly studied in randomized, controlled trials in acute bipolar depression. Lamotrigine has also demonstrated significant efficacy in recent studies and has been approved by the FDA.

Antidepressant medication use and non-Hodgkin's lymphoma risk: no association.

Animal and human studies have suggested that antidepressant medications may be associated with several cancers. The authors evaluated the association between antidepressant medication use and the risk of non-Hodgkin's lymphoma using a Canadian population-based case-control study, the National Enhanced Cancer Surveillance Study. Non-Hodgkin's lymphoma cases (n=638) diagnosed in 1995-1996 were identified using the Ontario Cancer Registry, and controls (n=1,930) were identified from the Ontario Ministry of Finance Property Assessment Database. Antidepressant medication use was ascertained using a self-administered questionnaire. Multivariate logistic regression was used to estimate odds ratios. "Ever" use of antidepressant medications was not associated with non-Hodgkin's lymphoma risk. The odds ratio for non-Hodgkin's lymphoma with 25 or more months of tricyclic antidepressant medication use was 1.6; however, this was nonsignificant. Duration or history of use or individual types of antidepressant medications were not associated with non-Hodgkin's lymphoma risk. These findings do not support an increased risk of non-Hodgkin's lymphoma with antidepressant medication use.

Psychiatric issues in older cancer patients.

Although many patients are surviving longer than in the past, a cancer diagnosis may shatter the dream of a dignified old age for elderly patients. Cancer diagnosis and treatment often produce psychologic stresses resulting from the actual symptoms of the disease, as well as perceptions of the disease and its stigma. Concerns related to cancer have particular meaning for aging individuals who undergo these situations in the context of retirement, widowhood, other medical disabilities and other losses. Today, patients and families are more interested in treatment issues, and quality of life, both during and after treatment. In this article we discuss late life depression, anxiety and delirium as they relate to elderly patients coping with cancer.