Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments.

Lammers CH, Diaz J, Schwartz JC, Sokoloff P.

Laboratoire de Physiologie, Universite Rene Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France.

The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10889548&dopt=Abstract antidepressant




Suboptimal use of antidepressants in the elderly: a population-based study in Nova Scotia.

Rojas-Fernandez C, Thomas VS, Carver D, Tonks R.

Division of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

This descriptive, retrospective, population-based study assessed patterns of antidepressant medication use in elderly patients in Nova Scotia during fiscal years 1993 through 1996. Individuals > or =65 years of age who were registered with Nova Scotia's Seniors Pharmacare program and filled a prescription for an antidepressant medication during the specified period were included in the study. We determined the number of individuals who filled > or =1 prescription for an antidepressant, the number whose prescription for an antidepressant could be matched with a diagnosis of depression in the physician's billing database, the number who used antidepressants that were judged inappropriate based on published criteria for medication prescribing in the elderly, the number who used a therapeutic antidepressant dose based on published dosing guidelines for the elderly, and the number who used antidepressants for > or =6 months. A total of 12,048, 12,317, and 13,419 individuals filled prescriptions for antidepressants during the 1993 to 1994, 1994 to 1995, and 1995 to 1996 fiscal years, respectively. In each fiscal year, approximately 70% had received a diagnosis of depression based on the International Classification of Diseases, Ninth Revision, Clinical Modification, making it likely that 70% of antidepressant users were receiving these drugs for a primary diagnosis of depression. The number of antidepressant prescriptions that were classified as inappropriate for use in the elderly was 67% in 1993 to 1994, 61% in 1994 to 1995, and 55% in 1995 to 1996. These decreases over time were statistically significant (P < 0.001). Among those using serotonin reuptake inhibitors, secondary tricyclic antidepressants, or tertiary tricyclic antidepressants, 79%, 45%, and 31%, respectively, appeared to be using therapeutic doses. Of 23,553 antidepressant treatment courses, 11,028 (47%) were for < or =180 days. During the study, a significant number of elderly individuals were prescribed antidepressant medications that are judged by expert consensus to be inappropriate for use in this population because of an unfavorable toxicity profile, although the number declined significantly from year to year (P < 0.001 for year-to-year comparisons). Many individuals also appeared to be using antidepressant doses that are probably subtherapeutic, but this finding seemed heavily dependent on the class of antidepressant used. Nearly half of the individuals studied appeared to be treated for inadequately short periods.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10890265&dopt=Abstract antidepressant




Fatal toxicity associated with antidepressant use in primary care.

Mason J, Freemantle N, Eccles M.

Centre for Health Economics, University of York.

BACKGROUND: New selective serotonin reuptake inhibitors (SSRIs) are perceived to be much safer in use than older tricyclic antidepressants (TCAs). However, previous assessments of association with fatal toxicity were made too soon after the introduction of the new drugs to permit accurate estimation. AIM: To determine the level of association of antidepressant drugs with fatal poisoning in the treatment of depression. METHOD: National data for England and Wales for three years (1993 to 1995) for fatal poisonings associated with antidepressants were obtained and, together with national primary care data on prescribing, were used to calculate fatality association by antidepressant drug. RESULTS: There were substantial variations between drugs in the level of association with fatal poisoning. Assuming an average treatment episode lasted three months, one fatality is associated with 11,800 treatment episodes of antidepressant use (95% CI = 11,120 to 12,580) when only single substance fatalities are considered. For SSRIs as a group the association was one in 411,800 (95% CI = 243,300 to 1.34 million) and for TCAs one in 8130 (95% CI = 7650 to 8670). However, for one of the newer TCAs, lofepramine, the single substance fatality rate associated with its use was one in 233,700 (95% CI = 124,500 to 1.89 million), which is not statistically significantly different from the SSRIs (P = 0.35). CONCLUSIONS: Estimated death rates associated with specific antidepressants should be compared with caution because drugs may be used selectively in patients with differing severity of depression. The proportion of these fatalities that could be prevented by switching to safer antidepressants is unclear when so few deaths are recorded as accidental; when there is intent to do self-harm the potential for switching to other means is unknown. However, this approach to relative toxicity may remain the best available since it is unlikely that a randomised trial will ever be conducted with a large enough sample size to obtain experimental data. Fatalities from antidepressant poisoning are very rare but if safety is paramount then lofepramine or an SSRI are justifiable treatment choices.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10897532&dopt=Abstract antidepressant




Improving the precision of primary care physician self-report of antidepressant prescribing.

Oxman TE, Korsen N, Hartley D, Sengupta A, Bartels S, Forester B.

Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. oxman dartmouth.edu

BACKGROUND: Methods to select physicians most likely to benefit from educational interventions to improve the outcome of depression have not been adequately developed. OBJECTIVE: The purpose of this study was to identify a combination of primary care provider (PCP) self-report questions to improve the precision of PCP estimates of actual antidepressant prescribing as a potential tool for PCP selection. METHODS: The total number of new and refill antidepressant prescriptions written by 124 PCPs and actually filled at pharmacies over a 2-year period were matched with telephone survey results of these PCPs completed before the 2-year period. Multiple regression techniques were used to identify a set of variables that improved upon PCPs' self-report of prescriptions. RESULTS: The mean for PCP-reported antidepressant prescriptions written in the last week was 7.8 (+/-11.2). The average weekly prescriptions actually filled was 6.72 (+/-5.65). Most survey variables were significantly correlated with antidepressant prescriptions. The final model included 6 variables that explained 52% of the variance in prescriptions. In addition to PCP-reported number of antidepressants prescribed, average number of primary care patients seen per week and number of patients covered by managed care were directly related to the volume of prescriptions. PCP age, percentage of patients referred immediately without treatment, and mental health services being too far away were inversely related. CONCLUSIONS: PCP self-reports on antidepressant prescribing are reasonably accurate proxies of actual prescribing. The precision of estimates of actual prescribing can be improved by considering practice structural and financial characteristics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10901360&dopt=Abstract antidepressant




Antidepressant treatment during social challenge prior to 1 year of age affects immune and endocrine responses in adult macaques.

Laudenslager ML, Clarke AS.

Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO 80220, USA. mark.laudenslager uchsc.edu

Antidepressants are widely used in treating depression and other behavioral problems in children and adolescents. Little is known about the long-term effects of these agents, particularly on physiological systems. The effects of previous antidepressant treatment during a social challenge in 9-month-old rhesus monkeys (Macaca mulatta) on their adult immune and endocrine responses were studied. Prior to the social challenge, the monkeys were reared either by their mother or in a peer group. Monkeys were treated with either a serotonergic agonist (fluoxetine), a noradrenergic agonist (desipramine), or saline during social separation. Non-separated, saline-treated monkeys served as control monkeys. In order to evaluate immune effects of early antidepressant treatment, adult monkeys were immunized with a novel antigen, tetanus toxoid. Blood samples were collected prior to and at 4-5-day intervals for 28 days after immunization. Plasma total immunoglobulins (IgG and IgM), complement levels (C3 and C4), tetanus antibody titers, and cortisol were assessed. Antibody levels were lowest in monkeys treated with antidepressants regardless of specific drug treatment or early rearing condition. Drug-treated subjects had elevated plasma immunoglobulins and complement protein levels. Cortisol was also highest in drug-treated subjects. These results should be considered when prescribing commonly used antidepressants for treatment of childhood disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10904120&dopt=Abstract antidepressant




Depression diagnoses and antidepressant use in primary care practices: a study from the Practice Partner Research Network (PPRNet).

Ornstein S, Stuart G, Jenkins R.

Department of Family Medicine and the Center for Health Care Research, Medical University of South Carolina, Charleston, USA.

BACKGROUND: We examined the pharmacologic management and follow-up of adults with newly diagnosed depression, and the use of antidepressants among patients not diagnosed with depression in primary care practice. A total of 389 physicians in 39 practices in the Practice Partner Research Network (PPRNet), a national network of primary care physicians provided data for the study. METHODS: We performed a retrospective cohort study for the year 1996 using demographic, contact, diagnosis, and prescription data available in the December 1997 PPRNet database. We identified patients with new diagnoses of depression from the problem lists in the electronic medical record. Psychopharmacologic agents prescribed within 5 days of the diagnosis, follow-up contacts within 6 months of the diagnosis, and diagnoses of patients prescribed antidepressants without a new diagnosis of depression were also identified. We performed descriptive analyses for all practices and for individual practices. RESULTS: During 1996, there were 149,327 active adult patients in the 39 participating practices. Of the 131,141 patients without a history of depression or antidepressant prescription, 2103 (1.6%) had a new diagnosis of depression in 1996. Incidence among the 39 practices ranged from 0.4% to 4.0%. Forty-nine percent of the newly diagnosed patients received an antidepressant prescription within 5 days of diagnosis; 81% of the prescriptions were for selective serotonin reuptake inhibitors. Ninety percent of the patients prescribed antidepressants had at least one contact in the 6 months after diagnosis (mean = 5.3 contacts). One third of the patients who had not begun antidepressants within 5 days of their diagnoses started taking one by the end of 1996. Among the 149,327 active patients, 6.3% received a prescription for an antidepressant in 1996. More than 40% of these patients had never been diagnosed with depression. CONCLUSIONS: Our study highlights the high prevalence and wide interpractice variations of diagnosing depression and prescribing antidepressants in primary care. Follow-up of patients newly diagnosed with depression was common and consistent with published guidelines. Opportunities for increased detection and treatment of depression exist in approximately half of the study practices.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10678342&dopt=Abstract antidepressant




Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.

Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr, Jones RM, Portoghese PS, Carlezon WA Jr.

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

We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12649385&dopt=Abstract antidepressant




Racial variation in antidepressant treatment in a Medicaid population.

Melfi CA, Croghan TW, Hanna MP, Robinson RL.

Eli Lilly and Company, Indianapolis, Ind. 46285, USA. melfi lilly.com

BACKGROUND: Many studies have found racial and socioeconomic variation in medical care for a variety of conditions. Undertreatment of depression for individuals of all races is a concern, but especially may affect vulnerable populations such as Medicaid recipients and minorities. With this study, we examine racial differences in the antidepressant usage in a Medicaid population. METHOD: Treatment of 13,065 depressed patients (ICD-9-CM criteria) was examined in a state Medicaid database covering the years 1989 through 1994. Treatment differences were assessed in terms of whether an antidepressant was received at the time of the initial depression diagnosis and the type of antidepressant prescribed (tricyclic antidepressants [TCAs] vs. selective serotonin reuptake inhibitors [SSRIs]), using logistic regression techniques. RESULTS: African Americans were less likely than whites to receive an antidepressant at the time of their initial depression diagnosis (27.2% vs. 44.0%, p < .001). Of those receiving an antidepressant, whites were more likely than African Americans to receive SSRIs versus TCAs. These findings remained even after adjusting for other covariates. CONCLUSION: Despite the easy availability of effective treatments, we found that only a small portion of depressed Medicaid recipients receive adequate usage of antidepressants. Within this Medicaid population, limited access to treatment was especially pronounced among African Americans. Racial differences existed in terms of whether an antidepressant was received and the type of medication used.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10695640&dopt=Abstract antidepressant