The effect of chronic administration of antidepressants on the circadian pattern of corticosterone in the rat.

Gomez F, Grauges P, Martin M, Armario A.

Departament de Biologia Celilular i de Fisiologia, Universitat Autonoma de Barcelona, Bellaterra, Spain.

Although antidepressant administration has been reported to alter the pituitary adrenal (PA) axis, the results are puzzling. In the present work, two possible factors contributing to these contradictory results were studied in adult male Sprague-Dawley rats: (i) the type of antidepressant and (ii) the time of day at which samples were taken. Samples were taken under nonstressful conditions. In expt 1, the acute effects of two doses (10 and 20 mg/kg) of the tricyclics clomipramine (CMI), desipramine (DMI) and imipramine (IMI), and the non-specific monoamine oxidase inhibitor (MAOI) phenelzine were studied. Only phenelzine increased plasma corticosterone with the low dose, whereas phenelzine and DMI increased plasma corticosterone with the high doses when measured 30 min after drug administration. In a second experiment, it was observed that after 12 daily doses of the drugs (20 mg/kg), all drugs increased plasma corticosterone at 30 min after the last drug administration. When the circadian pattern of corticosterone was studied in the same experiment, starting on the day after the last drug administration, a significant interaction of drug by time of day was found. Drugs caused changes in the normal levels of plasma corticosterone at certain times and DMI, IMI and phenelzine reduced the number of rats showing the normal corticosterone peak at 1900 hours. No significant effect of drugs on corticosteroid-binding globulin (CBG) was found. In a third experiment, phenelzine and IMI were administered as before, but samples were taken at several times both on the day of the last drug administration and on the following day. The two drugs altered the normal circadian pattern of corticosterone in a somewhat different way, but both caused a reduction of the corticosterone peak at lights off on the day after the last drug administration. The normal relative thymus weight observed in all groups (exp. 2) suggests that the overall biological activity of corticosterone was probably not affected by antidepressants. The present results indicate that most antidepressants are able acutely to activate the PA axis after repeated administration in a similar way or even more-strongly than after the first administration, and that some of these drugs alter normal circadian pattern of corticosterone. No evidence for decreased resting PA activity was found in antidepressant-treated rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9860102&dopt=Abstract antidepressant




Gaps in antidepressant prescribing in primary care in the United Kingdom.

Hylan TR, Dunn RL, Tepner RG, Meurgey F.

Fli Lilly and Company, Indianapolis, Indiana 46285, USA. hylant lilly.com

An important determinant for achieving efficacy results in clinical practice comparable to those demonstrated in clinical trials is whether or not patients take their medication as prescribed. Recent studies have shown that 30-60% of patients do not take their medications as prescribed. Gaps between antidepressant prescriptions raise questions about the possibility of periods of nonadherence to medication in clinical practice. The purpose of conducting this study was to assess the likelihood of experiencing a gap of > 15 days between antidepressant prescriptions for patients with a depression-related diagnosis and to assess whether this likelihood varied across different antidepressants with tricyclic antidepressants and selective serotonin reuptake inhibitors. Episodes of antidepressant treatment were constructed using the Doctors' Independent Network general practitioner medical records database. For all antidepressant agents considered, approximately 50% of patients had a gap between prescriptions and 15-25% of patients had a gap of > 15 days between prescriptions. A significant proportion of patients in a general practitioner setting in the UK have gaps recorded of > 15 days between antidepressant prescriptions. Gaps between prescriptions raise the question of whether patients may be at risk for clinical consequences associated with nonadherence to therapy, such as reduced effectiveness or treatment interruption symptomatology.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9861573&dopt=Abstract antidepressant




Antidepressants inhibit the glucocorticoid stimulation of thyrotropin releasing hormone expression in cultured hypothalamic neurons.

Jackson IM, Luo LG.

Division of Endocrinology, Rhode Island Hospital, Brown University School of Medicine, Providence 02903, USA.

BACKGROUND: The pituitary thyroid axis is frequently effected in human depression possibly due to alteration in hypothalamic thyrotropin releasing hormone (TRH) secretion. Since clinical recovery is associated with normalization of thyroid function, the direct effect of antidepressants on TRH expression in a well established fetal rat hypothalamic neuronal culture system was investigated. METHODS: Fetal rat hypothalamic neurons (day 17) in culture were treated with different concentrations of antidepressants with or without glucocorticoids for 7 days following which TRH content was measured by radioimmunoassay (RIA). RESULTS: The results showed that Imipramine (IMIP), a tricyclic antidepressant (TCA), decreased the TRH content in a dose-dependent manner (from 80.7 +/- 4.9, at 10(-9) mol/L, to 14.1 +/- 0.6, at 10(-5) mol/L, fmol/well; P < 0.05). Desipramine (DESI), another tricyclic antidepressant, also decreased the TRH content (from 63.6 +/- 2.5, at 10(-9) mol/L, to 12.6 +/- 0.4, at 10(-5) mol/L, fmol/well; P < 0.05). Sertraline (SERT) and Fluoxetine (FLUO), serotonin selective reuptake inhibitors (SSRI), also decreased TRH content in a dose dependent manner (from 83.9 +/- 7.9, at 10(-10) mol/L, to 7.6 +/- 0.4, at 10(-5) mol/L, and from 41.66 +/- 2.5, at 10(-8) mol/L, to 17.54 +/- 0.92, at 10(-6) mol/L, fmol/well, respectively; both P < 0.05). We then tested the effect of these antidepressants on the Dex stimulation of TRH content. IMIP, DESIP and FLUO at 10(-6) mol/L reduced the TRH response to glucocorticoid stimulation (36.4 +/- 4.0, 56.6 +/- 2.4, 23.75 +/- 4.0, respectively vs 107 +/- 7.5 fmol/well; P < 0.05). CONCLUSION: This raises the possibility that the enhanced thyroid function in depression, which we postulate, may result in part from glucocorticoid stimulation of TRH gene expression, can be reversed by antidepressants through a direct effect on the TRH neuron. However, other mechanisms may need to be invoked in addition since basal TRH content was also reduced.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9861783&dopt=Abstract antidepressant




The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression.

Melfi CA, Chawla AJ, Croghan TW, Hanna MP, Kennedy S, Sredl K.

Health Outcomes Evaluation Group, Eli Lilly & Co, Indianapolis, Ind 46285, USA. melfi lilly.com

BACKGROUND: Depression is associated with high rates of relapse and recurrence during a patient's lifetime. Current guidelines regarding treatment recommend 4 to 9 months of continuation antidepressant therapy following remission of acute symptoms to allow more complete resolution of the episode. In this article, we test whether adherence to these recommendations reduces the likelihood of relapse or recurrence in a Medicaid population. METHODS: We used a Medicaid database covering 1989 through 1994. The sample consists of the 4052 adult patients who filled an antidepressant prescription at the time of an initial diagnosis of depression. These patients were followed up for up to 2 years. Timing and counts of antidepressant prescription claims are used to construct a proxy measure for adherence to guidelines. Relapse or recurrence is defined by evidence of a new episode requiring antidepressant treatment, hospital admission for depression, electroconvulsive therapy, emergency department visit for mental health, or attempted suicide. We used survival analysis to predict relapse or recurrence for each patient and to examine the effect of following treatment guidelines on relapse and recurrence. RESULTS: Approximately one fourth of the patients had a relapse or recurrence during their follow-up period. Factors that affect relapse and recurrence include comorbidities, race, and guideline adherence. Those who continued therapy with their initial antidepressant were least likely to experience relapse or recurrence; those who discontinued their antidepressant early were most likely to experience relapse or recurrence. CONCLUSION: Adherence to depression treatment guidelines with an antidepressant that is likely to have continuous use by patients reduces the probability of relapse or recurrence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9862557&dopt=Abstract antidepressant




Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Holmes A, Yang RJ, Murphy DL, Crawley JN.

Section on Behavioral Genomics, National Institute of Mental Health, NIH, Bethesda, MD 20892-1375, USA. aholmes intra.nimh.nih.gov

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12464448&dopt=Abstract antidepressant




Inadequate dosaging in general practice of tricyclic vs. other antidepressants for depression.

Isometsa E, Seppala I, Henriksson M, Kekki P, Lonnqvist J.

Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland.

Several prescription database studies suggest major differences between antidepressants in the proportion of patients in general practice treated with doses likely to elicit a true drug response. However, in these studies it has been difficult to differentiate prescriptions for depression from those for other indications, or to distinguish lower starting doses from the final treatment doses. We investigated possible differences between types of antidepressant in the proportions of patients receiving adequate treatment doses for depression from the primary health care services of Helsinki. Doctors at 22 (71%) of the 31 health centres in Helsinki were surveyed with regard to their antidepressant prescriptions over a period of 2 working weeks. There were marked differences in dosaging adequacy between the various types of antidepressant prescribed for depression at final treatment doses. Overall, 71% of the prescriptions for the tricyclic antidepressants, but only 13% of those for the other antidepressants, mainly selective serotonin reuptake inhibitors, were for low doses that are generally considered to be ineffective (P<0.001). These findings endorse the emerging perception that, in general practice, tricyclic antidepressants are usually prescribed for depression in too low doses, and that a greater reliance on other antidepressants would probably improve the effectiveness of treatment in primary health care.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9879786&dopt=Abstract antidepressant




Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms.

Takahashi M, Terwilliger R, Lane C, Mezes PS, Conti M, Duman RS.

Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity were significantly increased in rat frontal cortex by chronic administration of each of the four classes of antidepressants. We also found that antidepressant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and reward that could also contribute to the anhedonia often observed in depressed patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic administration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system. The possibility that targeted inhibition of these PDE4 subtypes may produce an antidepressant effect is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9880581&dopt=Abstract antidepressant




Repeated trimipramine induces dopamine D2/D3 and alpha1-adrenergic up-regulation.

Maj J, Rogoz Z, Skuza G, Margas W.

Institute of Pharmacology, Polish Academy of Sciences, Krakow.

Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce beta-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and alpha1-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (+)-7-hydroxy-dipropyloaminotetralin (dopamine D2 and D3 effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an alpha1-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D2 and D3 (locomotor activity but not stereotypy) as well as alpha1-adrenergic receptors to their agonists. A question arises whether the reuptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9660111&dopt=Abstract antidepressant