Use of dopamine-beta-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs.

Cryan JF, Dalvi A, Jin SH, Hirsch BR, Lucki I, Thomas SA.

Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.

Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-beta-hydroxylase gene (Dbh). To specifically test the role of NE in mediating behavioral changes elicited by antidepressants, these mice were examined in the forced swim test. There was no difference in baseline immobility scores in the forced swim test between Dbh(+/-) mice, which have normal levels of NE, and Dbh(-/-) mice. However, the Dbh(-/-) mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in the Dbh(-/-) mice following pretreatment with the synthetic NE precursor L-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data show that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11454927&dopt=Abstract antidepressant




Resident physician management of Hispanic and non-Hispanic white patients on antidepressants.

Sleath B, Rubin RH, Huston S.

School of Pharmacy, University of North Carolina at Chapel Hill, 27599-7360, USA. betsy_sleath unc.edu

OBJECTIVE: The purpose of this study was to examine how well resident physicians monitored Hispanic and non-Hispanic white patients who were prescribed antidepressant medication. METHOD: Retrospective and prospective review of patients' medical records. SETTING: Family practice and internal medicine clinics at the University of New Mexico Health Sciences Center. PARTICIPANTS: Twenty-six resident physicians and 109 of their Hispanic and non-Hispanic white patients who were prescribed antidepressant medication when recruited into the study between March and December 1995. MAIN OUTCOME MEASURES: (i) Whether a physician recorded an appropriate diagnosis in the patient's chart, scheduled a follow-up visit and saw the patient for a follow-up visit within four weeks of the antidepressant being prescribed, and (ii) whether a physician recorded an adequate treatment plan, a discussion of side-effects and a discussion of how well the medication was working on the date the patient was enrolled in the study. RESULTS: Twenty-seven percent of patients were prescribed antidepressant medication. Less than half of the patients who were prescribed an antidepressant had a follow-up visit scheduled and only about one-third of patients were seen by their physician within one month of the antidepressant being prescribed. Physicians documented an adequate treatment plan in the charts of 51.1% of patients, a discussion of side-effects in 11.1% of charts and an assessment of how well the medication was working in 33.3% of charts. Younger patients and patients in better emotional health were more likely to have an adequate treatment plan documented in their chart. Patients in poorer physical health were more likely to have an adequate treatment plan documented in their chart along with a description of the effectiveness of the medication. Hispanic and non-Hispanic white patients who were prescribed antidepressants were monitored equally well by their primary care physicians. CONCLUSION: Primary care resident physicians need further training on the importance of monitoring patients on antidepressant medication.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11476147&dopt=Abstract antidepressant




Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients.

Rodriguez de la Torre B, Dreher J, Malevany I, Bagli M, Kolbinger M, Omran H, Luderitz B, Rao ML.

Departments of Psychiatry and Psychotherapy, University of Bonn, Germany.

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Whereas cardiovascular effects have occasionally been reported during controlled studies with SSRIs, TCA treatment poses a well-known problem in this respect. To investigate the putative correlation between antidepressant dose or serum levels and adverse effects, the authors devised a naturalistic study to evaluate the tricyclic antidepressants' and SSRIs' effect on the cardiovascular system. The authors also compared antidepressant serum levels to adverse effects. Inpatients treated with TCAs or SSRIs were included; an electrocardiogram (ECG) and a Schellong test were carried out on the day patients entered the hospital and during steady-state treatment with antidepressant drugs when blood was drawn for therapeutic drug monitoring. The patient population consisted of 114 acutely depressed patients; 81 patients were treated with TCAs and 33 with SSRIs. The TCAs comprised amitriptyline (n = 43), clomipramine (n = 11), doxepin (n = 19) and imipramine (n = 8); the SSRIs comprised fluvoxamine (n = 14) and paroxetine (n = 19). In TCA-treated patients, the authors observed the same type of abnormalities in conduction and orthostatic hypotension as had been observed earlier. The authors also observed cases of first-degree atrioventricular block, prolonged QTc interval, and orthostatic hypotension in SSRI-treated patients. Thus SSRIs also appear to affect the cardiovascular system, which might pose a problem for patients with preexisting conduction disease. The authors observed a strong correlation between the decrease in systolic pressure and antidepressant serum concentration (except for clomipramine and paroxetine), suggesting that antidepressant serum level is a better correlate than dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11477329&dopt=Abstract antidepressant




Selection of antidepressant drugs in general practice.

Mahendru RK, Mahendru S.

Psychiatric Division, GSVM Medical College, Kanpur.

Depression is a common psychiatric illness and since majority of patients suffering from depression are first seen and treated by general practitioners, it is important for them to identify and treat depressive illness more effectively. Fortunately, depression is a treatable condition. Identifying the optimal antidepressant agent requires careful consideration of the patient's age, health status, and history of response to antidepressants. Other considerations include adverse effect profile, cost of drug therapy and convenient dosage schedule. Selective serotonin reuptake inhibitors are well tolerated and are considered by many to be the agents of choice in primary care treatment of depression because of their favourable adverse effect profile. Heterocyclic antidepressants are preferred in elderly patients and patients with medical problems. Tricyclic antidepressants can also be of great help specially to younger group of patients and patients who have failed to respond to other antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11480958&dopt=Abstract antidepressant




Urban-rural patterns of increasing antidepressant use among nursing facility residents.

Rigler SK, Perera S, Redford L, Studenski S, Brown EF, Wallace D, Webb M.

Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS 66160-7117, USA.

OBJECTIVE: To characterize changing patterns of antidepressant use in nursing facilities across the urban-rural continuum during the mid-1990s. DESIGN: Retrospective analysis of antidepressant drug codes and demographic/clinical data from the Minimum Data Set (MDS) 1994 to 1997. SETTING: Kansas nursing facilities. PARTICIPANTS: Facility residents aged 65 and older. MEASUREMENTS: We examined (1) admission use and (2) after-admission use for newer and older antidepressants for each year separately, using a 4-stratum system to classify nursing facility location by county, from urban to most rural. Incidence rate ratios were determined for antidepressant use in each stratum using the urban strata as the reference. RESULTS: Remarkable increases in use of newer antidepressants were seen over time in all strata, but use was highest in the urban area. Modest urban-rural gradient effects attenuated over time and were not consistently seen across analyses and years. Tricyclic antidepressant (TCA) use remained largely unchanged over time and at much lower rates than newer agents. However, TCA use was also modestly higher in urban areas. Differences were clearer for use after admission, in contrast with admission use patterns. CONCLUSIONS: Newer antidepressants were rapidly adopted across the urban-rural continuum from 1994 to 1997. Marked increases in both admission and after-admission use of newer antidepressants were seen. Both newer and older antidepressants were used at modestly higher rates in urban areas. Further work is needed to elucidate the patient, prescriber, and facility factors that explain these prescribing patterns.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12807577&dopt=Abstract antidepressant




Methodological issues in clinical trials of antidepressant medications: perspectives from psychotherapy outcome research.

Gaudiano BA, Herbert JD.

Department of Psychiatry and Human Behavior, Brown University School of Medicine and Butler Hospital, Providence, RI 02906, USA. Brandon_Gaudiano brown.edu

Despite their widespread use, the specific efficacy of antidepressant medications has been a source of debate in recent years. Examination of the literature reveals that a significant proportion of the benefit produced in antidepressant trials is duplicated in pill placebo conditions. Furthermore, early trials utilizing active placebos, or medications that mimic the common side effects of antidepressants, showed even smaller differences as compared with active medications. We examine issues surrounding the use of placebo control conditions in antidepressant trials, including the pros and cons of active placebos. We conclude that similar challenges are faced by psychotherapy outcome researchers who have focused more on the separation of specific from nonspecific treatment factors and on the effects of researcher allegiance and patient expectancy on outcome. Within this context, recommendations for improving future antidepressant research are discussed. Copyright 2005 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15627852&dopt=Abstract antidepressant




Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs.

Malberg JE, Schechter LE.

Neuroscience Discovery, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. malberj1 wyeth.com

The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15638755&dopt=Abstract antidepressant




Animal models of depressive illness: the importance of chronic drug treatment.

Mitchell PJ, Redfern PH.

Department of Pharmacy & Pharmacology, University of Bath, Bath, UK. P.J.Mitchell bath.ac.uk

A wide diversity of animal models has been used to examine antidepressant activity. These range from relatively simple models sensitive to acute treatment, to highly sophisticated models that reputedly model some aspect of depressive illness and which yield a positive response to prolonged, chronic, drug treatment. In recent years antidepressant drug research has focused on the search for antidepressant therapy that has a more rapid onset of action. To be relevant, therefore, animal models must measure the time course of drug action. This review examines the claims of animal models to be sensitive to chronic drug treatment and considers their relevance. First, the review addresses the criteria necessary to examine the validity of animal models of depressive illness. Second, those animal models sensitive to chronic antidepressant treatment are reviewed with respect to their validity as animal models of either depressive illness and/or antidepressant activity. In particular, the development and utility of two "ethologically-relevant" animal models, the resident-intruder and social hierarchy paradigms, are described in detail. These models of rodent social and agonistic behaviour demonstrate that acute and chronic treatment with antidepressant drugs (regardless of their acute pharmacological activity) induce diametrically opposite changes in rodent agonistic behaviour. It is argued that the common ability of chronic treatment to increase rodent aggression (which in turn results in increased hierarchical status in closed social groups) most likely reflects the increased assertiveness and associated externalization of emotions expressed during recovery from depressive illness. Finally, findings that relate observed behavioural changes to underlying neurochemical changes are briefly reviewed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15638757&dopt=Abstract antidepressant