Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones.

Okugawa G, Omori K, Suzukawa J, Fujiseki Y, Kinoshita T, Inagaki C.

Department of Pharmacology Kansai Medical University, Moriguchi, Osaka, Japan.

Since the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) in the hippocampus have been implicated in cortisol feedback of the hypothalamus-pituitary-adrenal (HPA) axis, abnormalities in those receptors might underlie the hyperactivity of the HPA axis described in patients with major depression. Animal studies have shown that long-term in-vivo treatment with antidepressants up-regulates hippocampal GR and/or MR, but it is not clear whether this up-regulation is evoked through a direct action of antidepressants on these receptors. We therefore examined the direct effects of long-term antidepressant treatment on GR binding and the levels of GR messenger RNA (mRNA) in primary cultures of rat hippocampal neurones. The time course of the effects of the tricyclic antidepressants desipramine and amitriptyline on GR binding, as assessed by [3H]dexamethasone binding using RU 28362, a specific agonist for GR, showed a biphasic mode of stimulation: desipramine significantly increased the GR binding with 2-day exposure by 36% over that in controls and by 99% and 60% with 10- and 14-day exposures, respectively. Amitriptyline also led to a significant increase in GR binding, with peaks at 2 (by 60%) and 14 days of exposure (by 60%). The effects of 14-day treatment with desipramine required at least the first 4-day exposure, and the first 10-day exposure was required for the full effect. Northern blot analysis demonstrated that the GR mRNA level was significantly increased by 14-day treatment with desipramine (+142% over control), amitriptyline (+108%), mianserin (+124%), paroxetine (+42%) and sulpiride (+92%), but not with haloperidol. Immunocytochemistry for GR revealed that 2- or 14-day treatment with desipramine significantly increased the number of GR-positive cells with dominant immunoreactivity in the nuclei of granule cell-like neurones or in perikarya of pyramidal cell- and granule cell-like neurones. These findings suggest that tricyclic antidepressants directly increase hippocampal GR by short-term (2-day) and long-term (14-day) exposure, and that the increase by long-term exposure is evoked commonly with different classes of antidepressants through transcriptional up-regulation of GR expression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10520140&dopt=Abstract antidepressant




Cyclic vomiting syndrome in adults: clinical features and response to tricyclic antidepressants.

Prakash C, Clouse RE.

The Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.

OBJECTIVE: Cyclic vomiting syndrome (CVS) has been described infrequently in adults, and treatment in both children and adults remains unsatisfactory. We report clinical features of a group of adults with CVS and anecdotal outcome from open-label treatment with tricyclic antidepressants, medications that have some efficacy in other unexplained gastrointestinal disorders. METHODS: Clinical data were examined from 17 adult patients with CVS seen over a 10-yr period, each having been treated with a tricyclic antidepressant. Outpatient records were reviewed, clinical outcome was extracted using a priori criteria, and findings were compared with 37 patients having usual functional nausea and vomiting who also received tricyclic antidepressant therapy. RESULTS: Symptoms in CVS began at age 35 yr (range 14-73 yr); the average episode length was 6 days (range 1-21 days) and the symptom-free interval averaged 3.1 months (range 0.5-6 months). Vomiting cycles typically began without warning, and fewer than one-third of the subjects reported a prodrome or potential trigger event, such as menstrual periods, pregnancy, or large meals. Sleep was seemingly beneficial in 23.5%. Tricyclic antidepressant therapy was associated with complete remission in 17.6% and partial response in 58.8%, but was less effective than for functional nausea and vomiting (p = 0.02). CONCLUSIONS: CVS is a rare diagnosis with distinctive features in adults. Duration of episodes and cycles varies considerably across subjects. In open-label, uncontrolled use, tricyclic antidepressants appear beneficial for some subjects but are less effective in CVS than in chronic, persistent functional nausea and vomiting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10520833&dopt=Abstract antidepressant




[3H]-ketanserin binding and elevated plus-maze behavior after chronic antidepressant treatment in DSP-4 and P-CPA pretreated rats: evidence for partial involvement of 5-HT2A receptors.

Skrebuhhova T, Allikmets L, Matto V.

Department of Pharmacology, University of Tartu, Estonia.

[3H]-Ketanserin binding in rat neocortex (frontal and cerebral cortex) after 3-week treatment with desipramine (10 mg/kg) and citalopram (5 mg/kg) in vehicle-, DSP-4- (50 mg/kg) and p-CPA- (350 mg/kg before the beginning of experiments and once per week on the first and second week plus 100 mg/kg in the last week) pretreated rats was measured. The antidepressant activity of DSP-4 and p-CPA was evaluated indirectly using the elevated plus-maze test. Acute antidepressant treatment revealed an anxiogenic effect while chronic treatment elicited an anxiolytic effect. DSP-4 and p-CPA pretreatment elicited an antiexploratory effect that was not blocked by acute antidepressant treatment. After 3 weeks of antidepressant treatment, only desipramine + DSP-4 or p-CPA treatment revealed an antiexploratory effect. Three-week antidepressant treatment downregulated [3H]-ketanserin binding in the cerebral cortex. Citalopram treatment partially reversed p-CPA-induced downregulation of [3H]-ketanserin binding in rat whole neocortex. In conclusion, our experiments suggest that the 5-HT2A receptors in monoamine-impaired rats are involved in the mediation of antidepressant-induced behavioral phenomena, but chronic antidepressant treatment downregulates [3H]-ketanserin binding independently from the state of monoaminergic neurotransmission.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10544393&dopt=Abstract antidepressant




Are antidepressants all the same? Surveying the opinions of Australian psychiatrists.

Hickie IB, Scott EM, Davenport TA.

Academic Department of Psychiatry, St George Hospital, New South Wales, Australia. i.hickie unsw.edu.au

OBJECTIVE: Controlled trials do not suggest differences in efficacy between antidepressant compounds. Psychiatrists, however, frequently express the view that real differences do exist and are relevant to clinical practice. Since multiple comparative trials are not feasible, an alternative method for expanding the evidence base is to survey regularly the opinions of practising psychiatrists. METHOD: Two surveys of psychiatrists' opinions were conducted. Participants in the first survey were drawn from contact with 'SPHERE: A National Depression Project', while those in the second survey responded to a brief questionnaire distributed with Australasian Psychiatry. RESULTS: Reported volumes of scripts written, ratings of efficacy and tolerability, and preferences in specific clinical situations indicate that clinical psychiatrists now strongly prefer the newer antidepressant agents. They rate serotonin and noradrenalin re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs) highest for antidepressant efficacy, serotonin receptor subtype 2 (5HT2) antagonists and some SSRIs highest for anti-anxiety efficacy, and some SSRIs and reversible inhibitors of monoamine oxidase inhibitor-A (RIMAs) lowest for side-effect burden. Further, SSRIs were their first preferences for most clinical situations. Serotonin and noradrenalin re-uptake inhibitors were the preferred choice for treatment-resistant depression and patients who had failed to respond to one SSRI. Serotonin receptor subtype 2 antagonists were the second choice to SSRIs for mixed anxiety and depression, and major depression with sleep disturbance. Reversible inhibitors of monoamine oxidase inhibitor-A were the second choice to SSRIs for adolescents with major depression, patients aged over 65 years, patients with serious medical illnesses and patients with chronic fatigue. Tricyclic antidepressants (TCAs) were the preferred choice for patients with chronic pain, and second choice to SSRIs for patients with major depression with panic disorder, postnatal disorders and patients with psychotic depression. CONCLUSION: Psychiatrists believe that important differences do exist between available antidepressant compounds. Such opinions are divergent from limited controlled data but may be influenced by a wide range of factors other than direct clinical experience. The role of such surveys in ongoing evaluation of clinical practice is emphasised.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10544987&dopt=Abstract antidepressant




Use of antidepressants among Canadian workers receiving depression-related short-term disability benefits.

Dewa CS, Hoch JS, Goering P, Lin E, Paterson M.

Health Systems Research and Counseling Unit, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. carolyn_dewa camh.net

OBJECTIVES: Little is known about how antidepressants are being used, but rising antidepressant expenditures and the accompanying impulse to control costs make this a critical issue to be addressed. The authors studied patterns of antidepressant use in a population of workers receiving depression-related short-term disability benefits to determine whether populations likely to benefit from antidepressants are using them and, if so, whether they are using them in a way that the benefits from their use are maximized. METHODS: The analyses were based on 1996-1998 administrative data from short-term disability and prescription drug benefit claims and occupational health department records for employees of three Canadian companies. RESULTS: Approximately 58 percent of employees who were receiving depression-related short-term disability benefits had made at least one antidepressant claim. Employees who did not use antidepressants typically reported significantly fewer symptoms at baseline on average than those who did. About 91 percent of the employees who used antidepressants filled at least one prescription for a guideline-recommended first-line agent. Approximately 79 percent of antidepressant dosages reflected those suggested by the Canadian Network for Mood and Anxiety Treatment, and three timeframe indicators suggested that most patients used antidepressants within the recommended timeframes. CONCLUSIONS: The results of this study represent an important first step in exploring the question of how antidepressants are used among workers with depression-related disability. For the most part, these workers and those whose depression was more severe were more likely to obtain antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12719505&dopt=Abstract antidepressant




The effectiveness of antidepressants in elderly depressed outpatients: a prospective case series study.

Mittmann N, Herrmann N, Shulman KI, Silver IL, Busto UE, Borden EK, Naranjo CA, Shear NH.

HOPE Research Centre, Division of Clinical Pharmacology, Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada. mittmann srcl.sunnybrook.utoronto.ca

BACKGROUND: This study examined the effectiveness of antidepressants in a group of elderly depressed outpatients by assessing depression prevalence and recording adverse events over time. METHOD: A prospective practice-based observational study (1991-1994) included consecutive outpatients at least 65 years of age with a DSM-III-R diagnosis of major affective disorder and who were prescribed antidepressant medications. Depressive symptoms were examined over time (stage 1 = 0 to 2 months; stage 2 = 2 to 6 months; stage 3 = 6 months to 2 years) with the Montgomery-Asberg Depression Rating Scale (MADRS). The cutoff scores of MADRS <18 and MADRS > or =18 were used in survival statistics. Adverse events were recorded systematically. RESULTS: A total of 213 patients were seen over 2677 visits (mean +/- SD age = 75.5+/-6.1 years). MADRS scores for 85.8% of patients declined to below 18 within the first 2 months of antidepressant treatment. MADRS scores were above 18 for 37.3% of patients after 6 months and for 37.1% after 2 years. The mean time to decline in MADRS scores to below 18 in stage 1 was 36.1 days, and there was a significant difference between the antidepressant classes (log rank = 8.3, df = 3, p = .04), with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)/reversible inhibitors of monoamine oxidase A (RIMAs) having shorter times to response. The mean time to reach scores above cutoff during stage 2 was 144.3 days (log rank = 5.7, df = 3, p = .13) and during stage 3, 538.6 days (log rank = 9.8, df = 3, p = .02). Patients receiving TCAs and MAOIs/RIMAs had longer durations of MADRS scores below cutoff during stage 3 than those taking atypical antidepressants and selective serotonin reuptake inhibitors. All antidepressant classes reported similar adverse event profiles. CONCLUSION: This study systematically examined antidepressant effectiveness in a prospective design. TCAs and MAOIs/RIMAs were shown to be superior in effectiveness during 2 of the 3 treatment stages.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10549686&dopt=Abstract antidepressant




Antidepressant drug use in Italy since the introduction of SSRIs: national trends, regional differences and impact on suicide rates.

Barbui C, Campomori A, D'Avanzo B, Negri E, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. barbui irfmn.mnegri.it

Little is known about the use of antidepressant drugs in Italy since the introduction of selective serotonin reuptake inhibitors (SSRIs). To fill this gap, we examined antidepressant drug sales data from 1988 to 1996 for the whole country, and for the years 1995 and 1996 on the regional level. National suicide trends from 1988 to 1994 were also examined to assess whether the increasing use of SSRI antidepressants was associated with changes in suicide rates. From 1988 to 1996 an increase of antidepressant sales of 53% was recorded. This increase reflected increasing use of SSRIs, which in 1996 accounted for more than 30% of total antidepressants sold. The analysis of regional differences demonstrated heterogeneity between north, center, and south. In the south prescriptions of antidepressants and use of SSRIs were lower than in the rest of the country. In the 7-year period over which SSRI use increased, male suicide rates increased from 9.8 to 10.2 per 100,000 inhabitants, and female suicide rates declined from 3.9 to 3.2 per 100,000. These data suggest that SSRIs gave a new impetus to antidepressant sales. However, possible public health benefits related to the shift from old to new antidepressants have yet to be demonstrated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10327841&dopt=Abstract antidepressant




Predictors of antidepressant prescription and early use among depressed outpatients.

Sirey JA, Meyers BS, Bruce ML, Alexopoulos GS, Perlick DA, Raue P.

Department of Psychiatry, New York Presbyterian Hospital, White Plains 10605, USA. sirey%westnyh nyh.med.cornell.edu

OBJECTIVE: The rates of antidepressant recommendation and use were determined in outpatients with major depression receiving services in mental health clinics. Site of service and the patients' sociodemographic and clinical characteristics were investigated as possible predictors. METHOD: Patients admitted to six outpatient clinics were recruited through a two-stage sampling procedure. Patients with major depressive disorder (N = 124) according to the Structured Clinical Interview for DSM-IV--Patient Edition were assessed at admission and 3 months later. RESULTS: Drug therapy was recommended for most patients (71%), and minimal use (at least 1 week) was recorded for 59% of the subjects. White patients were nearly three times as likely to receive a recommendation for antidepressants. Antidepressant recommendation was also associated with severity of depressed mood, recent medication use, and clinic type. Recent antidepressant use was the only variable that predicted whether the patient actually took the recommended medication. CONCLUSIONS: Many patients with depression seeking treatment at community mental health clinics do not receive antidepressant drug therapy. The offer of medication is predicted by patient ethnicity, clinic type, and symptom severity. Minority patients are less likely to be offered antidepressant treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10327900&dopt=Abstract antidepressant