Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice.

Khisti RT, Chopde CT.

Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 010, Maharashtra, India. rtkhisti nagpur.dot.net.in

The present study demonstrated the antidepressant-like effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT(1B/1C) receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT(2A/1C) receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3alpha, 5alpha THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3alpha, 5alpha THP. Such a potentiating effect of the 5-HT(1A) or the 5-HT(2A/1C) receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s. c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300x3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3alpha, 5alpha THP. The accelerated effect of 3alpha, 5alpha THP in presence of serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3alpha, 5alpha THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10821935&dopt=Abstract antidepressant




Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine.

Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM.

Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Ontario, Canada. sidney_kennedy camh.net

BACKGROUND: Recent reports suggest that adverse effects on sexual function occur in up to 50% of patients who are treated with selective serotonin reuptake inhibitor (SSRI) antidepressants. Previously cited low rates were more likely a function of underreporting than underoccurrence. There is less evidence about rates of dysfunction with serotonin-norepinephrine reuptake inhibitor (SNRI) and reversible inhibitor of monoamine oxidase A (RIMA) antidepressants. The purpose of this report is to evaluate disturbances in sexual drive/desire and arousal/orgasm in 107 patients who met criteria for major depressive disorder and received treatment with either moclobemide, paroxetine, sertraline, or venlafaxine. METHOD: All consenting eligible patients who met DSM-IV criteria for major depressive disorder completed the Sexual Functioning Questionnaire, version 1 (SFQ) and were assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D) prior to and after 8 or 14 weeks of antidepressant therapy. Analyses were carried out to examine the effect of gender, drug type, pretreatment level of sexual dysfunction, and drug response on reported sexual dysfunction. RESULTS: Compared with women, men experienced a significantly greater level of drug-related impairment in drive/desire (p < .05), whereas there were no statistically significant differences in levels of arousal/orgasm impairment between men and women. The reported impairment in drive/desire items for men ranged from 38% to 50% and from 26% to 32% for women. No differences were found across the 4 antidepressants in men, whereas in women, rates of dysfunction were generally higher with sertraline and paroxetine, but only significantly so in comparison with moclobemide on some measures (p < .03). Rates of sexual dysfunction with venlafaxine tended to fall between those of SSRIs and the RIMA agent. An unexpected relationship was found between favorable drug response and a decreased level of drug-induced sexual dysfunction. CONCLUSION: Antidepressant-induced sexual dysfunction occurs in approximately 30% to 70% of patients who are treated with sertraline or paroxetine. Lower rates are reported with moclobemide and venlafaxine. Clinicians should evaluate the various aspects of sexual dysfunction before and during antidepressant therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10830148&dopt=Abstract antidepressant




The treatment of depression in UK general practice: selective serotonin reuptake inhibitors and tricyclic antidepressants compared.

Lawrenson RA, Tyrer F, Newson RB, Farmer RD.

European Institute of Health and Medical Sciences, University of Surrey, Surrey GU2 5RF, Guildford, UK. r.lawrenson surrey.ac.uk

BACKGROUND: Antidepressants are commonly prescribed by general practitioners as treatment for depression. Controversy exists as to the effectiveness in everyday use of the older tricyclic antidepressants (TCAs) when compared to the newer selective serotonin reuptake inhibitors (SSRIs). AIM: To investigate the patterns of current prescribing of antidepressants for the treatment of depression and compare TCAs with the newer SSRIs. METHOD: The study population was patients attending 151 computerised general practices from throughout the United Kingdom between 1991 and 1996. Patients with new prescriptions for antidepressants and a diagnosis of depression were identified. Age and gender distributions, prescribed doses and drop-out rates were investigated. RESULTS: During the study period 9.8% of patients received a prescription for an antidepressant, there was a 40% increase in the prescribing rate of TCAs and a 460% increase in SSRI prescribing. TCAs were initially prescribed in sub-therapeutic doses. More than 50% of patients ceased taking their antidepressants within 6 weeks of starting treatment. Fluoxetine and paroxetine were more likely to be prescribed for a therapeutic period than were other antidepressants. CONCLUSIONS: General practitioners should prescribe a therapeutic dose of antidepressant for a recognised therapeutic period to ensure that patients with depression receive the most effective treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10837883&dopt=Abstract antidepressant




Antidepressant treatment and health services utilization among HIV-infected medicaid patients diagnosed with depression.

Sambamoorthi U, Walkup J, Olfson M, Crystal S.

Institute for Health, Health Care Policy, and Aging Research, Rutgers University, New Brunswick, NJ 08901, USA. sambamoo rci.rutgers.edu

OBJECTIVE: To characterize the prevalence and predictors of diagnosed depression among persons with HIV on Medicaid and antidepressant treatment among those diagnosed, and to compare utilization and costs between depressed HIV-infected individuals treated with and without antidepressant medications. DESIGN: Merged Medicaid and surveillance data were used to compare health services utilized by depressed individuals who were or were not treated with antidepressant medications, controlling for other characteristics. SETTING AND PARTICIPANTS: The study population comprised Medicaid recipients in New Jersey who were diagnosed with HIV or AIDS by March 1996 and received Medicaid services between 1991 and 1996. MEASUREMENTS AND MAIN RESULTS: Logistic regression and ordinary least squares regressions were employed. Women were more likely and African Americans were less likely to be diagnosed with depression. Women and drug users in treatment were more likely to receive antidepressant treatment. Depressed patients treated with antidepressants were more likely to receive antiretroviral treatment than those not treated with antidepressants. Monthly total expenditures were significantly lower for individuals diagnosed with depression and receiving antidepressant therapy than for those not treated with antidepressants. After controlling for socioeconomic and clinical characteristics, treatment with antidepressant medications was associated with a 24% reduction in monthly total health care costs. CONCLUSIONS: Depressed HIV-infected patients treated with antidepressants were more likely than untreated subjects to receive appropriate care for their HIV disease. Antidepressant therapy for treatment of depression is associated with a significantly lower monthly cost of medical care services.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10840266&dopt=Abstract antidepressant




Antidepressant medication use and breast cancer risk.

Cotterchio M, Kreiger N, Darlington G, Steingart A.

Division of Preventive Oncology, Cancer Care Ontario, Toronto, Canada.

Experimental and epidemiologic studies suggest that antidepressant medication use may be associated with breast cancer risk. This hypothesis was investigated using a population-based case-control study; cases diagnosed in 1995-1996 were identified using the Ontario Cancer Registry, and controls were randomly sampled from an Ontario Ministry of Finance database. Data were collected using a self-administered questionnaire, and multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals. Adjusted odds ratio estimates ranged from 0.7 to 0.8 and were not statistically significant for "ever" use of antidepressants, tricyclics, and selective serotonin reuptake inhibitors. Compared with no antidepressant use, use of tricyclic antidepressants for greater than 2 years' duration was associated with an elevated risk of breast cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI): 0.9, 5.0). Of the six most commonly reported antidepressant medications, only paroxetine use was associated with an increase in breast cancer risk (OR = 7.2, 95% CI: 0.9, 58.3). Results from this study do not support the hypothesis that "ever" use of any antidepressant medications is associated with breast cancer risk. Use of tricyclic medications for greater than 2 years, however, may be associated with a twofold elevation, and use of paroxetine may be associated with a substantial increase in breast cancer risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10853633&dopt=Abstract antidepressant




Antidepressant effects on GABA-stimulated 36Cl(-) influx in rat cerebral cortex are altered after treatment with GABA(A) receptor antisense oligodeoxynucleotides.

Malatynska E, Crites GJ, Harrawood D, Goldenberg R, Matheson GK.

Indiana University School of Medicine, Department of Pharmacology and Toxicology, 8600 University Boulevard, Evansville, IN 47712, USA. emalatyn iupui.edu

Antidepressants act at the GABA(A) receptor to inhibit GABA-stimulated 36Cl(-) influx and GABA reduction of [35S]TBPS binding. This study examined how selective knock-down (via antisense oligodeoxynucleotides, aODNs) of GABA(A) receptor subunits modified antidepressant activity. The specific aODNs used were for the alpha1, beta1, beta2 or gamma2 subunits of the GABA(A) receptor. The aODN microinjections reduced corresponding GABA(A) receptor subunit mRNA levels by 30-40% as assessed by RT-PCR. The inhibitory effect of the antidepressants amitriptyline and mianserin on GABA-stimulated 36Cl(-) influx was decreased after microinjections of alpha1, beta1, or beta2 subunit aODNs but potentiated after microinjections of gamma2 subunit aODNs. This pattern of aODNs effect on amitriptyline and mianserin modulation of GABA-stimulated 36Cl(-) influx was the same for both antidepressants and similar to GABA but different than that of diazepam and bicuculline. We conclude that multiple subunits of the GABA(A) receptor regulate the effect of amitriptyline and mianserin on the GABA(A) receptor chloride ionophore complex. However, the exact identity of the subunit mediating the direct or allosteric modulation of the antidepressant effect on GABA-stimulated 36Cl(-) influx remains unclear.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10865061&dopt=Abstract antidepressant




Antidepressants preferentially enhance habituation to novelty in the olfactory bulbectomized rat.

Mar A, Spreekmeester E, Rochford J.

Douglas Hospital Research Centre, Quebec, Canada.

RATIONALE: The mechanisms whereby antidepressant drugs exert their therapeutic effects remain unknown. Responses to stressful stimuli are currently thought to contribute to the onset and course of affective disorders. It has been postulated that antidepressants might act by ameliorating response patterns to challenging life events, such as processes of reactivity and/or habituation. OBJECTIVE: Using the olfactory bulbectomy (OBX) rat model, this study examined the effects of various antidepressants on measures of reactivity and habituation in behavioral tests assessing responses to novel stimuli. METHODS: Sham-operated and OBX rats received 21 daily injections of fluoxetine (10 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg), buspirone (3 mg/kg), or vehicle. Forty-eight hours after the last injection, animals were tested in the open field, elevated plus maze, and startle apparatus. For each test, time series data were collected and fit with exponential random effects models, in which estimated parameters assessed behavioral reactivity and habituation. RESULTS: Relative to sham controls, OBX rats displayed increased total locomotor activity in the open field and exhibited increased open arm behavior in the elevated plus maze. Through comparison with zinc sulfate-treated anosmic controls, these OBX-induced increases were attributed to both an augmentation of initial reactivity due to anosmia and an attenuation of the average rate of habituation. Chronic antidepressant treatment did not reduce the anosmia-related initial reactivity levels of OBX rats to that of sham controls. Rather, the antidepressants evoked their restorative effects by increasing the rate of habituation. CONCLUSIONS: These findings suggest that antidepressants restore normal responding by permitting more effective adaptation to novel stimuli.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10867976&dopt=Abstract antidepressant




Marked differences in antidepressant use by race in an elderly community sample: 1986-1996.

Blazer DG, Hybels CF, Simonsick EM, Hanlon JT.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. blaze001 mc.duke.edu

OBJECTIVE: Prescriptions of antidepressant medications have increased significantly over the past 15 years across the life cycle. One overall correlate of medication use in older adults is race, with African Americans using fewer medications than whites. Given the frequency of depressive symptoms among elderly populations, as well as the increased potential for adverse side effects from antidepressants, the relative contribution of race in the use of antidepressants is critical for determining well-designed studies. The authors analyzed data from a community-based cohort of elders followed for 10 years to determine the association of race to the use of antidepressants between 1986 and 1996, with control for known correlates of depression in late life. METHOD: Information on antidepressant use and demographic and health characteristics were obtained from a stratified, probability-based sample of 4,162 elders (equally distributed between African American and white community-dwelling subjects) in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. RESULTS: A total of 4.6% of whites and 2.3% of African Americans used antidepressants in 1986. Approximately 14.3% of whites and 5.0% of African Americans used antidepressants in 1996. In controlled analyses, the prevalence odds ratio for antidepressant use in whites, compared to African Americans, was 1. 76 in 1986 and 3.77 in 1996. CONCLUSIONS: African American elders are much less likely to take antidepressants, and the difference in use increased over the 10 years of the survey.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10873916&dopt=Abstract antidepressant