Risk of drug interaction: combination of antidepressants and other drugs.

Miyasaka LS, Atallah AN.

Universidade Federal de Sao Paulo, Sao Paulo, SP, Brasil. lincoln.dmed epm.br

OBJECTIVE: To assess the frequency of combination of antidepressants with other drugs and risk of drug interactions in the setting public hospital units in Brazil. METHODS: Prescriptions of all patients admitted to a public hospital from November 1996 to February 1997 were surveyed from the hospital's data processing center in S o Paulo, Brazil. A manual search of case notes of all patients admitted to the psychiatric unit from January 1993 to December 1995 and all patients registered in the affective disorders outpatient clinic in December 1996 was carried out. Patients taking any antidepressant were identified and concomitant use of drugs was checked. By means of a software program (Micromedex ) drug interactions were identified. RESULTS: Out of 6,844 patients admitted to the hospital, 63 (0.9%) used antidepressants and 16 (25.3%) were at risk of drug interaction. Out of 311 patients in the psychiatric unit, 63 (20.2%) used antidepressants and 13 of them (20.6%) were at risk. Out of 87 patients in the affective disorders outpatient clinic, 43 (49.4%) took antidepressants and 7 (16.2%) were at risk. In general, the use of antidepressants was recorded in 169 patients and 36 (21.3%) were at risk of drug interactions. Twenty different forms of combinations at risk of drug interactions were identified: four were classified as mild, 15 moderate and one severe interaction. CONCLUSION: In the hospital general units the number of drug interactions per patient was higher than in the psychiatric unit; and prescription for depression was lower than expected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12700843&dopt=Abstract antidepressant




Potential savings from splitting newer antidepressant medications.

Cohen CI, Cohen SI.

Division of Geriatric Psychiatry, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. cohen_c hscbklyn.edu

BACKGROUND: The newer antidepressants are among the most commonly prescribed classes of medications. A favourable adverse effect profile and approvals for a wider range of disorders than their predecessors have fostered the growth of these drugs. However, newer antidepressants are appreciably more expensive than older medications, and the annual prescription costs of newer drugs are expected to continue to rise at double-digit rates. The price structuring of these medications is largely independent of their pill strengths, and splitting higher strength pills may reduce the average cost per dose by nearly half. Therefore, various health organisations and consumers have been using pill splitting to reduce prescription costs. Antidepressants are well suited for pill splitting because their therapeutic effects depend upon long-term alterations in neurotransmitters, and small variations in dose are not critical. OBJECTIVE: To examine the potential savings for various purchasers - health organisations and consumers - that can be derived from pill splitting of newer antidepressants. DESIGN AND SETTING: Product review and simulation study in the US healthcare setting. METHODS: All new antidepressants with pill strengths that could be halved and were not in capsular or time-release forms were included. Expenditures for purchasers of these pills were calculated using a variety of factors, such as the level of discounting of official average wholesale costs, average retail costs and the site of prescription dispensing. RESULTS: Seven antidepressants were included. In 2000, 42% of the pills of these antidepressants were at strengths that permitted splitting. If all eligible prescriptions had utilised split doses, purchasers could have saved over dollars US1.7 billion. The bulk of the saving (dollars US1.5 billion) would have been realised by pill splitting of only three medications - sertraline, paroxetine and citalopram. DISCUSSION AND CONCLUSIONS: The economic rationale for pill splitting of antidepressants is compelling for both health organisations and individual consumers. The literature indicates that when pill-splitters are used or a pharmacy cuts the pills, patients are satisfied and compliance is not reduced. However, pill splitting may be inadvisable for some subgroups of patients with reduced cognition or sensory or motor impairment, or older persons on polypharmacy. Pill splitting can be facilitated by mandating manufacturers to score all tablets, requiring pharmacists to fill prescriptions for split doses, and giving pharmacists incentives for splitting pills for patients. Finally, large-scale studies should be undertaken to examine the clinical effectiveness of, and financial savings from, pill splitting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11994024&dopt=Abstract antidepressant




Venlafaxine versus stimulant therapy in patients with dual diagnosis ADD and depression.

Hornig-Rohan M, Amsterdam JD.

Depression Research Unit, University Science Center, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

BACKGROUND: Adult attention-deficit disorder (ADD) may either present as chronic depression or be comorbid with major depressive disorder (MDD). The present study examined treatment outcome with antidepressants and/or stimulants in adults with ADD who initially presented with a diagnosis of MDD. METHOD: Seventeen patients with comorbid MDD and ADD were identified: 65% had a history of hyperactivity in childhood, and 41% had a history of treatment nonresponse to two or more antidepressants. Retrospective analysis was performed with patients who received one of three treatments: (i) venlafaxine, bupropion, or tricyclic antidepressant (TCA) monotherapy; (ii) stimulant monotherapy; or (iii) stimulant plus antidepressant therapy. Outcome was based upon change in both MDD and ADD symptoms. RESULTS: Venlafaxine-treated patients (80%) versus patients taking stimulant therapy alone (33%) had at least a moderate reduction in both MDD and ADD symptoms (chi2=2.40, Fisher exact P=.13). Similarly, 88% of patients on stimulants plus antidepressant therapy also showed a reduction in both MDD and ADD symptoms (versus stimulant monotherapy) (chi2 = 7.22, Fisher exact P=.018). There was no difference in response rates between venlafaxine monotherapy and combination stimulant plus antidepressant therapy (chi2=0.13, Fisher exact p=ns). CONCLUSION: Although preliminary in nature, these data suggest that venlafaxine monotherapy may have similar efficacy to a treatment with a combination of stimulant plus antidepressant therapy, and superior to stimulant therapy alone, in patients with comorbid MDD and ADD. Controlled, prospective trials with larger patient samples will be needed to confirm these preliminary observations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11999912&dopt=Abstract antidepressant




Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants.

Nunes-Tavares N, Nery da Matta A, Batista e Silva CM, Araujo GM, Louro SR, Hasson-Voloch A.

Laboratorio de Fisico-Quimica Biologica, Instituto de Biofisica Carlos Chagas Filho, Universidade do Brasil, UFRJ, 21491-590 Rio de Janeiro, Brazil. nilnunta biof.ufrj.br

The effects of tricyclic antidepressants drugs (TCA) amitriptyline, imipramine and nortriptyline, on purified Electrophorus electricus (L.) acetylcholinesterase (AChE; acetylcholine hydrolase, EC 3.1.1.7) were studied using kinetic methods and specific fluorescent probe propidium. The antidepressants inhibited AChE activity by a non-competitive mechanism. Inhibition constants range from 200 to 400 microM. Dimethylated amitriptyline and imipramine were more potent inhibitors than the monomethylated nortriptyline. Fluorescence measurements using bis-quaternary ligand propidium were used to monitor ligand-binding properties of these cationic antidepressants to the AChE peripheral anionic site (PAS). This ligand exhibited an eight-fold fluorescence enhancement upon binding to the peripheral anionic site of AChE from E. electricus (L.) with K(D)=7 x 10(-7)M. It was observed that TCA drugs displaced propidium from the enzyme. On the basis of the displacement experiments antidepressant dissociation constants were determined. Similar values for the inhibition constants suggest that these drugs have similar affinity to the peripheral anionic site. The results also indicate that the catalytic active center of AChE does not participate in the interaction of enzyme with tricyclic antidepressants. These studies suggest that the binding site for tricyclic antidepressants is located at the peripheral anionic site of E. electricus (L.) acetylcholinesterase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12009302&dopt=Abstract antidepressant




Antidepressants inhibit human acetylcholinesterase and butyrylcholinesterase activity.

Muller TC, Rocha JB, Morsch VM, Neis RT, Schetinger MR.

Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900, RS, Brazil.

This study examines the effect of the antidepressants fluoxetine, sertraline and amitriptyline on cholinesterase (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) activities in human serum and erythrocyte membrane (ghost). The concentrations used range from 3 to 60 microM for fluoxetine and amitriptyline and 0.3 to 12 microM for sertraline. At the micromolar range concentration, different classes of antidepressants, including fluoxetine and sertraline (selective serotonin reuptake inhibitors (SSRIs)) and amitriptyline (tricyclic antidepressant) inhibited human serum cholinesterase. The order of inhibitory potency was sertraline>amitriptyline>>fluoxetine and the IC(50) values were 4.05, 9.43 and 62 microM, respectively. Analysis of kinetic data indicated that the inhibition caused by all the antidepressants was mixed in nature. At the micromolar range concentration, sertraline (60-120 microM) and amitriptyline (60-180 microM) inhibited human erythrocyte AChE. The order of inhibitory potency was sertraline>amitriptyline and the IC(50) values were 80 and 134 microM, respectively. Analysis of kinetic data indicated that the inhibition caused by all the antidepressants in AChE human erythrocyte membrane (ghost) was mixed in nature. The interaction of sertraline with the cholinesterase is labile since the removal of inhibitor by gel filtration recovered completely the enzyme activity. Our results demonstrate that the usual clinical antidepressants are inhibitors of the cholinesterases on human serum and erythrocyte membrane.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12009429&dopt=Abstract antidepressant




Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly.

Movig KL, Leufkens HG, Lenderink AW, Egberts AC.

Hospital Pharmacy Midden-Brabant, TweeSteden Hospital, Tilburg, The Netherlands. kmovig zamb.tsz.nl

BACKGROUND: Hyponatraemia may have serious clinical consequences. Several reports of hyponatraemia associated with the use of antidepressants have been published. However, it remains unclear whether a specific class or individual antidepressants are associated with an increased risk for hyponatraemia.OBJECTIVES: To investigate the association between the use of serotonergic antidepressant drugs and the occurrence of hyponatraemia compared with non-users of these agents and to determine the time-to-admission rate after initiation of these drugs.METHOD: A matched case-control study was conducted. Data were obtained from the PHARMO database including information on drug dispensing and hospital admission indications for 320,000 inhabitants of eight Dutch cities. Data from 1990 to 1998 were used. Case patients ( n=203) were all patients who were admitted to a hospital for hyponatraemia. Community controls ( n=608), matched by age and gender, were sampled within the same living area and calendar (index) date as the case patients. All patients were 18 years of age or older. Exposure to antidepressant drugs, classified as serotonergic versus non-serotonergic agents, and potential confounding factors were determined on the index date. Time-to-admission was defined as the period between start of the antidepressant drug and hospital admission. Conditional logistic regression model was used to estimate odds ratios (ORs) and to adjust for potential confounding factors.RESULTS: Ten (5%) case patients used serotonergic antidepressants compared with eight (1%) in the control group; compared with non-use, the risk for hyponatraemia was fourfold higher [OR 3.96; 95% confidence interval (CI) 1.33, 11.83] due to serotonergic antidepressant drug use. Risk for developing hyponatraemia was greatest in the first 2 weeks of serotonergic drug therapy.CONCLUSION: Use of serotonergic antidepressants is associated with the development of hyponatraemia. Hyponatraemia occurred during the first 2 weeks of treatment, which justifies blood-sodium monitoring during the first weeks after initial treatment with a serotonergic antidepressant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12012148&dopt=Abstract antidepressant




Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant.

Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA.

Department of Biological Sciences, California State University Los Angeles, 5151 State University Drive, Los Angeles, CA 90032, USA.

Antidepressants and physical exercise have been shown to increase the transcription of hippocampal brain-derived neurotrophic factor (BDNF). Much evidence regarding the initial actions of antidepressant medications as well as exercise leads to the hypothesis that noradrenergic (NE) and/or serotonergic (5-HT) activation is a key element in the BDNF transcriptional elevation common to both interventions. Currently, we used short-term beta-adrenergic, 5-HT(1A), or 5-HT(2A/C) receptor blockade to characterize the influence of NE and 5-HT systems on BDNF transcription during physical exercise and antidepressant treatment. In situ hybridization revealed that beta-adrenergic blockade significantly blunted the BDNF mRNA elevations due to exercise, and also inhibited the modest elevations in the CA3 and dentate gyrus following short-term treatment with tranylcypromine. In contrast, 5-HT(2A/C) blockade only minimally altered exercise-induced BDNF mRNA levels, but inhibited up-regulation of BDNF transcription via tranylcypromine. Finally, 5-HT(1A) blockade did not inhibit exercise-induced BDNF mRNA elevations, but significantly enhanced levels above those achieved with exercise alone in the CA4. These results suggest that NE activation via beta-adrenergic receptors may be essential for both exercise and antidepressant-induced BDNF regulation. 5-HT(1A) and 5-HT(2A/C) activation, on the other hand, appear to be most important for antidepressant-induced BDNF regulation, but may also participate significantly in exercise-induced regulation in the CA4.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12759116&dopt=Abstract antidepressant




Antidepressant-like effects of cytidine in the forced swim test in rats.

Carlezon WA, Pliakas AM, Parow AM, Detke MJ, Cohen BM, Renshaw PF.

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.

BACKGROUND: Altered brain phospholipid metabolism may be involved in the pathophysiology of cocaine dependence and mood disorders. Evidence suggests that citicoline, a rate-limiting metabolite for phospholipid synthesis, reduces cocaine craving in human addicts. Because antidepressants can reduce cocaine craving, we explored in rats the possibility that citicoline has antidepressant effects. We also tested the primary metabolites of citicoline, cytidine and choline. METHODS: We examined if citicoline or metabolites alter immobility in the forced swim test. We used two scoring methods: latency to become immobile, a simple method that identifies antidepressants, and behavioral sampling, a complex method that differentiates antidepressants according to pharmacological mechanisms. RESULTS: Over a range of doses, citicoline did not affect behavior in the forced swim test. At molar equivalent doses, cytidine dramatically decreased immobility, whereas choline tended to increase immobility. The effects of cytidine resemble those of desipramine, a standard tricyclic antidepressant. None of the treatments affected locomotor activity, and cytidine did not establish conditioned place preferences. CONCLUSIONS: Citicoline does not have effects in the forced swim test, but its primary metabolites have opposing effects: cytidine has antidepressant-like actions, whereas choline has prodepressant-like actions. At antidepressant doses, cytidine lacks stimulant and rewarding properties. This is the first report of potential antidepressant effects of cytidine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12022961&dopt=Abstract antidepressant