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PubMed2003

Adenosine A2A receptors and depression.

Adenosine and its analogues have been shown to induce "behavioral despair" in animal models believed to be relevant to depression. Recent data have shown that selective adenosine A2A receptor antagonists (e.g., SCH 58261, ZM241385, and KW6002) or genetic inactivation of the receptor was effective in reversing signs of behavioral despair in the tail suspension and forced swim tests, two screening procedures predictive of antidepressant activity. A2A antagonists were active in the tail suspension test using either mice previously screened for having high immobility scores or mice that were selectively bred for their spontaneous "helplessness" in this test. At stimulant doses, caffeine, a nonselective A1/A2A receptor antagonist, was effective in the forced swim test. The authors have hypothesized that the antidepressant-like effect of selective A2A antagonists is linked to an interaction with dopaminergic transmission, possibly in the frontal cortex. In support of this idea, administration of the dopamine D2 receptor antagonist haloperidol prevented antidepressant-like effects elicited by SCH 58261 in the forced swim test (putatively involving cortex), whereas it had no effect on stimulant motor effects of SCH 58261 (putatively linked to ventral striatum). The interaction profile of caffeine with haloperidol differed markedly from that of SCH 58261 in the forced swim and motor activity tests. Therefore, a clear-cut antidepressant-like effect could not be ascribed to caffeine. In conclusion, available data support the proposition that a selective blockade of the adenosine A2A receptor may be an interesting target for the development of effective antidepressant agents.

Adenosine↗
PubMed1999

Activation of the inflammatory response system: A new look at the etiopathogenesis of major depression.

Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects.

Journal Article↗
PubMed1976

The contribution of drug research to investigating the nature of endogenous depression.

A relationship between brain monamines and endogenous depression is suggested by observations on the mode of action of drugs producing or alleviating depressive symptoms. For example, reserpine is capable of faithfully mimicking the clinical picture of endogenous depression, which may be related to monoamine depletion. On the other hand, antidepressant drugs, e.g. the monoamine oxidase inhibitors, the tricyclic antidepressants and the monoamine precursors appear to increase the availability of monoamines at postsynaptic receptor sites. The different classes of antidepressant agents in general appear to potentiate each other's actions, according to animal data and clinical observations. Studies on the mode of action of tricyclic antidepressants with different profiles and on monoamine precursors suggest that 5-hydroxytryptamine is primarily involved in the control of mood, and noradrenaline in psychomotor activity. Clincial investigations initiated by the drug studies have demonstrated changes in monoamine metabolism in endogenous depression. The available evidence thus suggests a causal relationship between disturbances in monoamine metabolism and depression.

Animals↗
PubMed1992

Neurochemical alterations of serotonergic neuronal systems in depression.

A burgeoning literature has accumulated over the past three decades implicating alterations in central nervous system (CNS) serotonergic neurotransmission both in the pathophysiology of depression and in the mechanism and action of antidepressant drug treatment. Specifically, studies have revealed (1) decreases in brain concentrations of serotonin and decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in a sizeable subgroup of depressed patients; (2) alterations in both presynaptic and postsynaptic CNS serotonergic receptors in depressed patients; (3) alterations in putative peripheral markers of CNS serotonergic function such as platelet serotonin uptake, platelet [3H]imipramine or [3H]paroxetine binding, platelet 5-HT2 receptor density, and whole blood serotonin content in depressed patients; (4) that virtually all known antidepressant agents, regardless of their receptor-specific properties, have been shown to increase the efficacy of CNS serotonergic neurotransmission; (5) that in patients treated with antidepressants who exhibit a remission, rapid depletion of serotonin results in a prompt clinical relapse; and (6) that all known serotonin re-uptake blockers thus far studied have been demonstrated to be clinically effective antidepressant medications. The recent identification and cloning of multiple serotonergic receptor subtypes and the identification and cloning of the serotonin transporter offer further promise for elucidating the role of CNS serotonergic neurons in the pathogenesis of depression and, moreover, for the development of innovative treatment strategies for this disorder.

Antidepressive Agents↗
PubMedDate not supplied

Effect of thymoanaleptic agents on the course of experimental arterial hypertension and catecholamine content in tissues and urine.

Experimental hypertension was induced in rats by two methods. In the course of hypertension development the rats of experimental groups were treated with following tricyclic antidepressive agents: Imipramine, Opipramol, Amitriptylline and Nortriptylline injected in doses of 5.0 or 0.5 mg per 1 kg of body weight. Higher doses of the above drugs inhibited the development of hypertension, whereas the lower doses had no effect on arterial blood pressure.

Animals↗
PubMed1999

Antidepressant exacerbation of spasticity.

Patients with spinal cord injury (SCI) may develop depression. This may be related to adjustment to living with an SCI in addition to dealing with complications of the injury, such as spasticity. Pharmacologic treatment of depression can be difficult because of neurochemical and receptor changes that are associated with SCI. Newer antidepressant agents are purported to have selective activity by alteration of serotonergic neurotransmission. A case report is presented that illustrates exacerbation of spasticity by this family of antidepressant medications. Mechanisms possibly explaining this exacerbation of spasticity are the effects of serotonin on motor neuron and reflex activity, denervation supersensitivity, and the serotonin syndrome. Understanding the relationship between serotonergic systems and spasticity can be important in treating depression in patients with spasticity.

Adjustment Disorders↗
PubMed2002

Double-blind antiglucocorticoid treatment in schizophrenia and schizoaffective disorder: a pilot study.

BACKGROUND: Antiglucocorticoids, such as ketoconazole, have been investigated as antidepressant agents in major depression and other conditions. Despite evidence that a significant number of patients with schizophrenia and schizoaffective disorder are both hypercortisolemic and depressed, the antidepressant effects of antiglucocorticoids have never been assessed in these populations. METHODS: Fifteen symptomatic patients with diagnoses of schizophrenia or schizoaffective disorder, who were at least partially treatment-resistant, were treated with ketoconazole, up to 800 mg/day, (n = 8) or placebo (n = 7) for four weeks in a double-blind manner. The study medication was added to a pre-stabilized antipsychotic and/or antidepressant medication regimen. RESULTS: Ketoconazole treatment, compared to placebo, was associated with significant improvements in observer-rated depression, but not in subjectively rated depression, positive or negative psychotic symptom ratings, or cognitive performance scores. CONCLUSIONS: These pilot data partially support the hypothesis that antiglucocorticoids reduce depressive symptoms in patients with schizophrenia and schizoaffective disorder, although objective and subjective ratings may not be similarly affected during a four-week course of treatment. Further studies with larger sample sizes, more extensive endocrine assessments and longer duration of drug administration seem warranted.

Adult↗
PubMed1994

[Drug discontinuation in depression].

Before stopping or starting medications in depression, the first step is a through assessment of the patient's mood disorder: past medical general and psychiatric history, psychological profile, past specific treatment history... Today some data are well demonstrated: antidepressant or lithium or carbamazepine discontinuation should be done gradually (over weeks or months) and with an intensive medical follow-up; after the acute treatment of the index depressive episode, a full therapeutic dose of the antidepressant agent should be continued for at least 4 to 6 months; antipsychotic drugs and minor tranquilizers use should be limited: combination of a neuroleptic and an antidepressant in depression with psychotic features, combination of a minor tranquilizer in depression with anxiety during the first three weeks if necessary. A contario the timing and the method of discontinuing maintenance treatment (lithium or antidepressant) have not been well studied. Literature data are discussed: frequency of recurrence during treatment discontinuation, even after long-term euthymia; possible risk for developing rapid-cycles or non response after lithium discontinuation. More precise clinical guidelines are necessary.

Antidepressive Agents↗
PubMed2001

Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice.

1. Adenosine, an ubiquitous neuromodulator, and its analogues have been shown to produce 'depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been found to reverse adenosine-mediated 'depressant' effect. 2. We have designed studies to assess whether adenosine A2A receptor antagonists, or genetic inactivation of the receptor would be effective in established screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. 3. Adenosine A2A receptor knockout mice were found to be less sensitive to 'depressant' challenges than their wildtype littermates. Consistently, the adenosine A2A receptor blockers SCH 58261 (1 - 10 mg kg(-1), i.p.) and KW 6002 (0.1 - 10 mg kg(-1), p.o.) reduced the total immobility time in the tail suspension test. 4. The efficacy of adenosine A2A receptor antagonists in reducing immobility time in the tail suspension test was confirmed and extended in two groups of mice. Specifically, SCH 58261 (1 - 10 mg kg(-1)) and ZM 241385 (15 - 60 mg kg(-1)) were effective in mice previously screened for having high immobility time, while SCH 58261 at 10 mg kg(-1) reduced immobility of mice that were selectively bred for their spontaneous 'helplessness' in this assay. 5. Additional experiments were carried out using the forced swim test. SCH 58261 at 10 mg kg(-1) reduced the immobility time by 61%, while KW 6002 decreased the total immobility time at the doses of 1 and 10 mg kg(-1) by 75 and 79%, respectively. 6. Administration of the dopamine D2 receptor antagonist haloperidol (50 - 200 microg kg(-1) i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 mg kg(-1) i.p.) in forced swim test whereas it left unaltered its stimulant motor effects. 7. In conclusion, these data support the hypothesis that A2A receptor antagonists prolong escape-directed behaviour in two screening tests for antidepressants. Altogether the results support the hypothesis that blockade of the adenosine A2A receptor might be an interesting target for the development of effective antidepressant agents.

Animals↗
PubMed1999

Add-on polytherapy with antidepressants and its significance in inpatients with major depression.

Add-on polytherapy with antidepressant agents was reviewed in 42 inpatients with major depression diagnosed according to the ICD-10 criteria. Twenty-eight (67.7%) patients were treated with two or more antidepressants. The most frequent combination consisted of a tricyclic antidepressant and a non-tricyclic antidepressant. Nineteen (67.8%) patients of the polytherapy group were treated with a dosage equivalent to 150 mg/day of tricyclic antidepressant. Clinically, not every patient with major depression can tolerate the adverse side effects induced by an effective dose of a single tricyclic antidepressant. From this viewpoint, add-on polytherapy with antidepressants could be one of the treatment options, especially for such intolerant patients.

Adult↗
PubMed2001

Update in the therapeutic management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a remarkably frequent disorder that leads to relevant impairment in patients' quality of life. Four mechanisms are involved in the pathogenesis of IBS: altered intestinal motility; increased visceral sensitivity; disturbed intestinal reflexes (intrinsic and extrinsic), and psychological disorders. The close relationship between the central nervous system and the enteric nervous system (the brain-gut axis) is the basis of the actual research on IBS therapy. It is conceivable that in the near future a better understanding of IBS pathophysiology will help us to tailor treatment for different IBS patients. At the moment, the subclassification of the diverse patterns of symptomatology allows the adjustment of treatments for IBS according to the clinical predominance of each patient. Dietary modifications like fiber supplementation, antidiarrheal agents and antispasmodic drugs are the basis of the current treatment of IBS and depend on the predominant symptom (constipation, diarrhea or pain, respectively). If severe pain is present, antidepressant agents are an appropriate alternative. However, the scientific evidence supporting this current therapeutic approach is limited. Visceral analgesics and serotonin agonists and antagonists may play an important therapeutic role in the near future. However, it is not likely that one single treatment will help every IBS patient and many of them will need a more complex approach with multidisciplinary therapy (diet, psychotherapy, medications).

Analgesics↗
PubMed2002

Pathophysiology and treatment of hot flashes.

Hot flashes affect about three fourths of postmenopausal women and are one of the most common health problems in this demographic group. Dysfunction of central thermoregulatory centers caused by changes in estrogen levels at the time of menopause has long been postulated to be the cause of hot flashes. Treatment should begin with a careful patient history, with specific attention to the frequency and severity of hot flashes and their effect on the individual's function. For mild symptoms that do not interfere with sleep or daily function, behavioral changes in conjunction with vitamin E (800 IU/d) use is a reasonable initial approach. For more severe symptoms, the next step is to determine whether there is a contraindication or a personal reservation to estrogen replacement therapy. For women who are able and willing to use estrogen, it will successfully relieve symptoms by about 80% to 90%. In patients with a history of breast or uterine cancer, treatment with the progestational agent megesterol acetate appears to be a safe alternative that also decreases hot flashes by approximately 80%. For women unwilling or unable to use hormone therapy, one of the newer antidepressant agents can be prescribed. Venlafaxine decreases hot flashes by about 60%. Gabapentin is another drug that appears promising as therapy for women unable or unwilling to use estrogen, and the results of ongoing trials to determine its efficacy are eagerly awaited. The use of clonidine, methyldopa, and belladonna should be discouraged because of their modest efficacy and adverse effects.

Aged↗
PubMed1999

Substance P antagonists: the next breakthrough in treating depression?

Several lines of evidence implicate the neuropeptide substance P in depression, either in the pathogenesis or as a novel target for amelioration of symptoms. NK1 (substance P) receptor antagonists have been reported to have antidepressant-like actions in animal models. The first clinical trial of an NK1 antagonist showed promising results. A second trial, using a more potent compound, is underway. If the clinical trials show that NK1 (substance P) antagonism represents a well-tolerated, distinct mechanism for antidepressant activity, novel antidepressant agents will emerge as mono- or adjunct-therapy.

Animals↗
PubMed2002

Somatization as a predictor of medication discontinuation due to adverse events.

Medication discontinuation due to intolerable side-effects remains a significant clinical problem in the treatment of depression. We were unable to locate studies which found predictors of medication cessation due to side-effects. We posited that an identifiable subgroup of medically healthy, depressed adults who discontinued medication because of adverse events would have higher pre-treatment somatic symptoms than patients who completed a course of treatment. The sample (n =940) was drawn from a series of double-blind, placebo-controlled studies of antidepressants (imipramine, phenelelzine, L-deprenyl, mianserin and desipramine). Within the medication group, side-effect dropouts had more somatic symptoms than study completers and those who discontinued treatment for miscellaneous reasons. Within the placebo-treated group, the small number of subject who discontinued treated because of side-effects precluded valid statistical analyses, but the findings were in the same direction as those in the medication group. Clearly, further research is required to determine whether these results, obtained from a series of university-based clinical trials with healthy subjects, are generalizable to patients with significant comorbid medical and/or psychiatric disorders, treated with newer antidepressants agents in a general clinical practice setting.

Adult↗
PubMedDate not supplied

Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder.

BACKGROUND: This was an open-label, single-center study of the long-term efficacy and effectiveness of venlafaxine extended release (XR) in the treatment of chronic pain and depression in outpatients. All patients have been diagnosed with major depressive disorder (MDD) of various types, with or without chronic pain, and had previously failed treatment with either tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). METHODS: Efficacy of treatment was determined using the 21-item Hamilton Rating Scale for Depression (HAMD-21), the Visual Analogue Scale (VAS) for the evaluation of pain, and a 12-item quality of life scale (QOL). Patients were treated in an unblended open trial for 1 year with 150 mg or more of venlafaxine XR once daily. RESULTS: After 1 year of treatment, 21-item Hamilton Rating Scale for Depression, Visual Analogue Scale, and quality of life scores were significantly improved from permanent baseline scores. CONCLUSION: These data show long-term efficacy and effectiveness of venlafaxine XR, a serotonin (5-HT) and norepinephrine (NE) and dopamine (DA) reuptake inhibitor antidepressant agent, having analgesic properties.

Adult↗
PubMed1995

Paroxetine. A pharmacoeconomic evaluation of its use in depression.

There has been intense debate about whether the use of paroxetine or other selective serotonin reuptake inhibitors (SSRIs) as alternatives to tricyclic antidepressants for first-line treatment of depression can be justified, considering their higher acquisition costs. The rationale for using paroxetine in the treatment of depression lies in its more favourable tolerability profile than tricyclic antidepressants and its lower risk of death on overdosage. Depression is one of the most common psychiatric disorders and is associated with substantial direct, indirect and intangible costs. Indirect costs account for the majority of costs associated with depression, while drug costs account for only 9 to 25% of direct costs. Therefore, increased recognition and treatment of depression has the potential to greatly reduce the overall cost of this disease. Pharmacoeconomic data on paroxetine and other SSRIs in the treatment of depression are scarce. Available studies are limited to considerations of direct costs alone and are primarily based on retrospective data from clinical trials. Nevertheless, in terms of costs per successfully-treated patient, available data suggest that the treatment costs associated with paroxetine are similar to those of amitriptyline and possibly less than those of imipramine. Paroxetine treatment costs also appear to be similar to those of amitriptyline and imipramine in terms of expected costs per patient. While one group of investigators suggested that the overall cost of administering paroxetine may also be less than that for fluoxetine and sertraline when drug costs and labour costs associated with dosage adjustment are taken into account, more data are required before conclusions on the relative pharmacoeconomic merits of SSRIs can be made. Despite the lower risk of death from overdosage with SSRIs, switching from an established tricyclic antidepressant to a newer tricyclic or related antidepressant in an attempt to avoid suicide appears to be more cost effective than switching to an SSRI. Thus, evidence available to date indicate that despite higher acquisition costs paroxetine and other SSRIs are no more costly than tricyclic antidepressants when total costs per successfully treated patient or expected costs per patient are considered. With its favourable tolerability profile and low risk of death on overdosage, paroxetine should therefore be considered as an effective alternative to tricyclic antidepressant agents as a first-line treatment of depression.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents, Second-Generation↗
PubMed1996

Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium.

This study sought to investigate possible interactions between antidepressant agents and lysergic acid diethylamide (LSD) in humans through the use of retrospective questionnaires. Ten subjects were identified who used LSD during chronic (3 weeks or longer) periods of antidepressant administration. These subjects were asked to describe the phenomenological effects of self-administered hallucinogens prior to and during antidepressant treatment; a structured, standardized questionnaire was used to evaluate LSD experiences. Chronic tricyclic antidepressant administration was associated with subjective increases in physical, hallucinatory and psychological responses to LSD. Similarly, subjects receiving lithium chronically also reported increases in their responses to LSD. In contrast, subjects who had been chronically taking an monoamine oxidase (MAO) inhibitor reported subjective decreases in the effects of LSD. This is similar to a previous report by our group of a decreased response to LSD in individuals who were chronically taking serotonin-selective antidepressants. These altered responses to LSD most likely involve differential changes in central serotonin and dopamine receptor systems and are consistent with other recent data suggesting that the clinical efficacy of different classes of antidepressants may not necessarily rely on a common mechanism of action in the brain.

Adult↗