Expanding the horizons of depression: beyond the monoamine hypothesis.

Hindmarch I.

HPRU Medical Research Centre, University of Surrey, Egerton Road, Guildford, Surrey GU2 5XP, UK.

The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404573&dopt=Abstract antidepressant




Strategies for the rapid treatment of depression.

Miller FE.

Northwestern University Medical School, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA.

The purpose of this article is to review current literature relating to the determination of the time course of antidepressant effects. Further, this work explores studies examining the safety and effectiveness of pharmacological techniques for accelerating the therapeutic effects of antidepressant medication. A review of the literature pertaining to strategies for accelerating antidepressant medication effects was accomplished using the MEDLINE database, employing the key title words, antidepressant, rapid, and accelerating. A preponderance of evidence suggests that there is a multiple week latency for the onset of action of antidepressant medications. This latency appears to apply to virtually all standard antidepressants and may reflect slow adaptive changes to the inciting event of increased monoamine levels. Several strategies have received attention as potential strategies with which to accelerate the therapeutic effects of antidepressant medications. These include the use of high initial doses of some agents and also the use of initial augmentation strategies. Specifically, studies exist suggesting the acceleration of antidepressant effects using high initial doses of tricyclic antidepressants or venlafaxine, as well as the potential for acceleration by using initial augmentation with psychostimulants, lithium, or pindolol. Considering the morbidity and mortality associated with severe depression, a critical need exist for the exploration of ways in which to achieve antidepressant effects more quickly. A number of preliminary studies suggest strategies for the rapid treatment of depression, each with an apparent high degree of safety. Further investigations in more carefully defined patient populations and utilizing advances in the techniques for assessing antidepressant onset are needed. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404582&dopt=Abstract antidepressant




Limitations to enhancing the speed of onset of antidepressants - are rapid action antidepressants possible?

Artigas F.

Department of Neurochemistry, Institut d'Investigacions Biomediques de Barcelona, CSIC-IDIBAPS, Rossello 161, 08036 Barcelona, Spain.

Existing antidepressant treatments suffer from a limited efficacy and a slow onset of action. Some first-generation antidepressant drugs are still among the most effective treatments. Several neurobiological adaptive mechanisms are involved in the delayed action of antidepressants. Among these, a negative feed-back involving somatodendritic autoreceptors plays an important role in such delay. In the case of the SSRIs, the prevention of this effect with 5-HT(1A) autoreceptor antagonists enhances their effects at experimental level. Open-label and placebo-controlled trials with the mixed beta-adrenoceptor/5-HT(1A) antagonist pindolol support that this agent reduces the latency to achieve a clinical improvement when used in combination with SSRIs. Displacement studies support that this action is mediated by its interaction with 5-HT(1A) receptors. The design of clinical trials for the evaluation of fast-acting antidepressants is critical. The use of loose criteria of response may result in a poor discriminating power. Conversely, stringent clinical criteria may be more helpful in revealing the differences between treatments. The data of a double-blind, placebo-controlled trial comparing fluoxetine plus placebo and fluoxetine plus pindolol suggests that the use of sustained response (i.e., one maintained until the end of the trial) is critical for the establishment of differences between treatments. Other factors, such as a placebo lead-in phase or the frequency of visits, appear to play a minor role. Overall, these data indicate that faster antidepressant drugs can be obtained through a better knowledge of their actions in CNS. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404595&dopt=Abstract antidepressant




Antidepressant activity and calcium signaling cascades.

Paul IA.

Department of Psychiatry, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.

Although antidepressant treatments produce clear effects on monoaminergic neuronal function, the link between these effects and therapeutic response to treatment is controversial. Previous studies have demonstrated that antagonists of the NMDA receptor-gated calcium ionophore result in antidepressant-like responses in rodents and humans. Likewise, antidepressant treatments produce regionally selective adaptation of the NMDA receptor suggestive of diminished capacity to gate calcium into receptive neurons. Similarly, voltage-dependent calcium channel antagonists have been reported to produce antidepressant-like effects in rodents. A major target of increases in subcellular calcium concentration is nitric oxide synthase (NOS) which liberates NO in response to stimulation. Recently, we have demonstrated that nitric oxide synthase antagonists produced antidepressant-like response in both in vivo preclinical screening procedures and in post-mortem in vitro studies of beta-adrenoceptor density. We propose: 1) that interruption of the Ca(2+)-calmodulin-NOS-guanylyl cyclase subcellular signaling pathway at any point will produce antidepressant-like effects; 2) that the acute actions of antidepressants in preclinical screening procedures are a consequence of their ability to disrupt Ca(2+)-calmodulin-NOS-guanylyl cyclase signaling; 3) that chronic but, not acute treatment with antidepressants results in adaptation of the Ca(2+)-calmodulin-NOS-guanylyl cyclase signaling pathway; 4) that this adaptation is necessary for the achievement of the therapeutic actions of antidepressants and; 5) that major depression is accompanied by an alteration (hyperactivity?) of subcellular Ca(2+) signaling. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404601&dopt=Abstract antidepressant




The immunoregulatory effects of antidepressants.

Maes M.

Clinical Research Centre for Mental Health, Antwerp, Belgium.

There is some evidence that major depression is accompanied by activation of the inflammatory-response system (IRS). It has been hypothesized that increased production of proinflammatory cytokines may play a role in the etiology of major depression. If increased production of proinflammatory cytokines is at all involved in the etiology of depression, one would expect antidepressive treatments to have negative immunoregulatory effects. This paper reviews the effects of antidepressants, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), heterocyclic antidepressants (HCAs), serotonin-noradrenaline reuptake inhibitors (SNRIs), lithium, l-5-hydroxytroptophan (L-5-HTP), reversible inhibitors of MAO-A (RIMA) on the production of proinflammatory cytokines, e.g. interferon-gamma (IFNgamma), and negative immunoregulatory cytokines and agents, e.g. interleukin-10 (IL-10). In depressed patients, prolonged treatment with antidepressants and mood stabilizers normalizes signs of activation of the IRS, such as increased serum IL-6 and acute phase protein concentrations. In vitro, it has been shown that various types of antidepressive drugs, including TCAs (imipramine; clomipramine); SSRIs (citalopram, fluoxetine, sertraline); lithium; SNRIs (venlafaxine); HCAs (trazodone); RIMAs (moclobemide) and L-5-HTP significantly suppress the ratio of IFNgamma/IL-10 production by peripheral blood immunocytes. These antidepressant drugs appear to have a common effect on the IRS, i.e. in vitro they increase the production of IL-10 by peripheral blood leukocytes. Thus, the results suggest that antidepressants have negative immunoregulatory effects. It may be speculated that antidepressants exert some of their antidepressant effects through their negative immunoregulatory capacities. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404604&dopt=Abstract antidepressant




Unmet needs in the pharmacological management of depression.

Baldwin DS.

Department of Psychiatry, University of Southampton, Southampton, UK.

Newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (NRIs) and drugs acting on both serotonin and noradrenaline, represent a clinically significant advance over the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Nevertheless, all current pharmacological treatments for depression fall somewhat short of the 'ideal', and unmet needs remain in the pharmacological management of depression. In general, current antidepressants differ little in terms of efficacy. However, in terms of tolerability, SSRIs appear to offer clear advantages over older therapies. For example, the proportion of patients who discontinue treatment because of adverse events and the risk of fatal toxicity both appear to be lower with SSRIs, compared with TCAs. Some adverse events, however, such as sexual dysfunction and nausea (typical serotonergic side effects), tend to be more frequent with SSRIs. Also, individual SSRIs appear to differ in the likelihood that they will be associated with these side effects. However, no clear advantage emerges for any one SSRI over another, and the current recommendation is that the anticipated side-effect profile should be tailored to the patient. Current pharmacoeconomic data do not appear to favour any antidepressant over another, with no cost benefits associated with prescribing TCAs instead of SSRIs.The refinement of current drugs arising from the introduction of their active enantiomers may translate into clinical benefit, bringing closer the 'ideal' antidepressant. Potential benefits of a single enantiomer versus the racemate in the management of depression include: a reduction in the total dose, while maintaining desired outcomes, as well as a possible greater efficacy, dose for dose,simpler assessment of dose-response relationships,a reduction in pharmacokinetic and pharmacodynamic variability between patients, anda reduction in any toxicity arising from the inactive stereoisomer. However, these benefits remain to be proved in clinical trials and naturalistic studies. Further refinement of the benefit:risk ratio of current 'gold standard' drugs may go some way to addressing the shortfalls in existing antidepressant therapy. Copyright 2001 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12404714&dopt=Abstract antidepressant




Patterns of antidepressant use among children and adolescents.

Shireman TI, Olson BM, Dewan NA.

Pharmacoeconomics, Pharmacy Practice Department, University of Kansas School of Pharmacy, Lawrence 66045, USA. tshireman rx.pharm.ukans.edu

OBJECTIVE: The purpose of this study was to identify patterns of new antidepressant use among children and adolescents and to determine whether the duration of treatment was sufficient. METHODS: A retrospective 12-month analysis was conducted of claims data for a cohort of nine- to 18-year-old new users of antidepressants in an Ohio Medicaid population. Treatment duration was categorized into five time intervals reflecting initial treatment through various continuation periods. RESULTS: A total of 554 children and adolescents started an antidepressant regimen during a three-month period. These children were mostly Caucasians (78 percent), and their average age was 13 years. Boys and girls were equally represented. The use of antidepressants increased with age among girls but declined among boys. The distribution of antidepressants dispensed was selective serotonin reuptake inhibitors, 47 percent; tricyclic antidepressants, 27 percent; and other antidepressants, 23 percent. The specific agent used varied by primary psychiatric diagnosis. The proportion of children who completed treatment was 94 percent for the four-week treatment period, 23.5 percent for the six-month period, and 12.6 percent for the whole year. CONCLUSIONS: Antidepressants are used in the treatment of children and adolescents who have a wide array of mental health problems. As with adults, continuation of treatment among children and adolescents declines dramatically after an initial period. In addition to studies of the clinical efficacy of antidepressant use among children and adolescents, future research is needed to assess adherence to practice guidelines and health outcomes in childhood and adolescent mental health.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12407273&dopt=Abstract antidepressant




Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study.

Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G.

Motherisk Program, Division of Pediatrics and Psychology and the Reseaarch Institute, The Hospital for Sick Children, Toronta, Ont. Canada.

OBJECTIVE: Previous work suggested that first-trimester exposure to tricyclic antidepressants or fluoxetine does not affect adversely child IQ and language development. However, many women need antidepressants throughout pregnancy to avoid morbidity and suicide attempts. Little is known about the fetal safety of tricyclic antidepressants and fluoxetine when taken throughout pregnancy. The goal of this study was to assess the effects of tricyclic antidepressants and fluoxetine used throughout gestation on child IQ, language, and behavior. METHOD: In a prospective study, mother-child pairs exposed throughout gestation to tricyclic antidepressants (N=46) or fluoxetine (N=40) and an unexposed, not depressed comparison group (N=36) were blindly assessed. The three groups were compared in terms of the children's IQ, language, behavior, and temperament between ages 15 and 71 months. The authors adjusted for independent variables such as duration and severity of maternal depression, duration of pharmacological treatment, number of depression episodes after delivery, maternal IQ, socioeconomic status, cigarette smoking, and alcohol use. RESULTS: Neither tricyclic antidepressants nor fluoxetine adversely affected the child's global IQ, language development, or behavior. IQ was significantly and negatively associated with duration of depression, whereas language was negatively associated with number of depression episodes after delivery. CONCLUSIONS: Exposure to tricyclic antidepressants or fluoxetine throughout gestation does not appear to adversely affect cognition, language development, or the temperament of preschool and early-school children. In contrast, mothers' depression is associated with less cognitive and language achievement by their children. When needed, adequate antidepressant therapy should be instituted and maintained during pregnancy and postpartum.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411224&dopt=Abstract antidepressant