SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
This review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials.
Weight gain caused by antidepressant drugs is a major reason for patient noncompliance with treatment and poor treatment outcome. Knowing which drugs are more likely to cause weight gain in the short term and the long term is essential to any discussion with the patient about the risks vs the benefits of antidepressant therapy. Informing the patient up front about the chances of weight gain and what can be done if it occurs helps build a strong physician-patient relationship and promotes good treatment outcomes.
BACKGROUND: Up to 30% of patients with major depression fail to respond to an antidepressant trial, with most taking a selective serotonin reuptake inhibitor (SSRI) as initial treatment. While the tricyclic antidepressants might be effective for SSRI nonresponders, they have been relegated to third- and fourth-line treatment. This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression. METHOD: 92 patients with treatment-resistant DSM-III-R major depression, with resistance defined by at least 1, but no more than 5, well-documented adequate trials of antidepressants during the current episode, were treated openly with nortriptyline for 6 weeks. Patients were titrated up to full target doses of nortriptyline within 1 week, with target blood levels of 100 ng/mL. Response was defined as a 50% or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score. We performed an intent-to-treat analysis with the last observation carried forward. RESULTS: Approximately 40% of patients were responders (N = 39) and 12% were remitters (N = 11) after 6 weeks of nortriptyline. Over a third of patients were unable to complete the trial. CONCLUSION: Nortriptyline was effective for over a third of patients with treatment-resistant depression, and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants.
Explore the source record for details and available documents.
Depression is a widespread, recurrent disease that sometimes remains inadequately managed by current drug therapy. There is a need to develop better antidepressants that ideally would have a more rapid onset of action, a higher response rate, and improved long-term efficacy. The latest generation of antidepressants have novel dual modes of action, and the results of recent clinical trials indicate that they may have superior efficacy to established drug therapies such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Dual acting drugs, such as venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, have been shown to have a rapid onset of action. The long-term efficacy of mirtazapine and of venlafaxine was also found to be superior to that of TCAs. Pindolol was found to accelerate response to SSRI therapy. However, these results were dependent on the patient population. These studies clearly suggest that the latest generation of antidepressants offer a more rapid response to treatment, an improved response rate, and superior long-term efficacy than conventional therapy. The clinical importance of these results should not be overlooked.
Depression in the elderly and very elderly, especially those in long-term care facilities, often is more difficult to treat than depression in young or middle-aged adults. Because this population may be more sensitive to the common adverse effects of many antidepressant drugs, particularly the anticholinergic side effects, administration of pharmacologic therapy for depression in the elderly requires careful consideration of the side effect profiles of the various classes of antidepressant medication.
Because of the introduction and popularity of the selective serotonin reuptake inhibitor (SSRI) antidepressants, much attention was centered on the indolealkylamine 5-hydroxytryptamine, or serotonin. To some extent, this focus on serotonin occurred at the expense of the catecholamine neurotransmitter norepinephrine. Nevertheless, it has been apparent for almost 40 years that selective blockers of norepinephrine reuptake may be antidepressants (e.g., desipramine). This brief review covers the acute pharmacologic effects that may be responsible for the efficacy of currently marketed antidepressants as well as that of reboxetine, a newly developed selective norepinephrine reuptake inhibitor. Also discussed is the fact that the acute pharmacologic profile of selective reuptake inhibitors often predicts effects they produce when given long term. For example, the long-term administration of SSRIs produces certain effects on serotonergic systems, but not noradrenergic ones. By contrast, selective norepinephrine reuptake inhibitors, when given long term, modify certain noradrenergic parameters, but not serotonergic indices. Finally, it is speculated how drugs that enhance central noradrenergic transmission might ameliorate the symptoms of depression.
Various antidepressant drugs given repeatedly induce the supersensitivity of postsynaptic dopamine D2 and D3 receptors. Several reports have also suggested the subsensitivity of presynaptic dopamine D2 receptors. The aim of the present study was to investigate the effect of two antidepressant drugs with different pharmacological profile, i.e. imipramine and citalopram, administered repeatedly, on the hypoactivity induced by low dose (0.05 mg/kg sc) of (+/-)7-hydroxy-dipropylaminotetralin (7-OH-DPAT), a dopamine D3 receptor preferring agonist. Male Wistar rats were treated with antidepressant drugs (10 mg/kg po) either acutely (single dose) or repeatedly (twice daily for 14 days). Two or 24 h after the last dose of antidepressant drug, the locomotor activity induced by (+/-)7-OH-DPAT was measured in photoresistor actometers. Additionally, the influence of nafadotride (0.2 or 1 mg/kg ip), a dopamine D3 preferring antagonist, on the (+/-)7-OH-DPAT-induced changes in locomotor activity was studied. Low dose of (+/-)7-OH-DPAT induced the locomotor hypoactivity, however, this effect was not modulated by nafadotride. Antidepressant drugs given repeatedly, but not acutely, reversed the effect of (+/-)7-OH-DPAT, and this effect of antidepressants was antagonized by nafadotride. The obtained results indicate that the sensitivity of dopamine D3 receptors might be altered by the repeated treatment with antidepressant drugs.
The present study investigated the effects of the selective neurokinin-2 (NK2) receptor antagonist SR48968 in behavioral, electrophysiological, and biochemical tests sensitive to the action of prototypical antidepressants (fluoxetine, imipramine) or to corticotropin-releasing factor (CRF) receptor antagonists, which have been proposed recently as potential antidepressants. Results showed that SR48968 (0.3-10 mg/kg i.p.) produced antidepressant-like activity because it reduced immobility in the forced swimming test in both mice and rats, and decreased the amount of maternal separation-induced vocalizations in guinea pig pups. This latter effect appears to involve a reduction of stress-induced substance P release because SR48968 reduced the separation-induced increase in the number of neurons displaying neurokinin-1 receptor internalization in the amygdala. Furthermore, SR48968 increased the expression of the cAMP response-element binding protein mRNA in the rat hippocampus after repeated (1 mg/kg i.p., 21 days), but not acute administration. Finally, neuronal firing of the locus coeruleus (LC) and noradrenergic (NE) release in the prefrontal cortex both elicited by an uncontrollable stressor or an intraventricular administration of CRF were reduced by SR48968 (0.3-1 mg/kg i.p.). The finding that SR48968 (1 mg/kg i.p.) blocked the cortical release of NE induced by an intra-LC infusion of the preferential NK2 receptor agonist neurokinin A suggested the presence of NK2 receptors in this latter region. Importantly, SR48965 (1-10 mg/kg i.p.), the optical antipode of SR48968, which is devoid of affinity for the NK2 receptor, was inactive in all the models used. These data suggest that NK2 receptor blockade may constitute a novel mechanism in the treatment of depression and CRF-related disorders.
Explore the source record for details and available documents.
Caffeine is a marker drug for testing the activity of CYP1A2 (3-N-demethylation) in humans and rats. Moreover, it is also a relatively specific substrate of CYP3A (8-hydroxylation). In the case of 1-N- and in particular 7-N-demethylation of caffeine, apart from CYP1A2, other cytochrome P-450 isoenzymes play a considerable role. The aim of the present study was to investigate the influence of imipramine, amitriptyline and fluoxetine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that imipramine exerted a most potent inhibitory effect on caffeine metabolism. Imipramine decreased the rate of 3-N-, 1-N- and 7-N-demethylations, and 8-hydroxylation of caffeine, the effect on 3-N-demethylation being most pronounced (Ki = 33 microM). Amitriptyline showed distinct inhibition of 3-N- and 1-N-demethylation of caffeine, though its effect was less potent than in the case of imipramine (Ki = 57 and 61 pM, respectively). The influence of amitriptyline on 8-hydroxylation and especially on 7-N-demethylation of caffeine was weaker (Ki = 108 and 190 pM, respectively) than on 3-N- or 1-N-demethylation, suggesting a narrower spectrum of cytochrome P-450 inhibition by amitriptyline than by imipramine, involving mainly the subfamily CYP1A2, and--to a lesser degree--CYP3A. In contrast to the tested tricyclic antidepressants, fluoxetine did not exert any considerable effect on the 3-N- or 1-N-demethylation of caffeine (Ki = 152 and 196 microM, respectively), which indicates its low affinity for CYP1A2. However, fluoxetine displayed a clear inhibitory effect on caffeine 7-N-demethylation (Ki = 72 microM), the reaction which is catalyzed mainly by other than CYP1A2 isoenzymes. Fluoxetine diminished markedly the 8-hydroxylation of the marker drug; as reflected by Ki values, the potency of inhibition of rat CYP3A by fluoxetine was similar to that of imipramine (Ki = 40 and 45 microM, respectively). In summary, CYP1A2 was distinctly inhibited by imipramine and amitriptyline, CYP3A by imipramine and fluoxetine, while other CYP isoenzymes (CYP2B and/or 2E1) by imipramine and fluoxetine.
After withdrawal arrest in many heroin addicts, they displayed the syndrome of anhedonia including affective disorders (depression, dysphoria, anxiety), dyssomnia and a pathologic craving for opiates. Anhedonia is often the cause for recurrence in heroine addiction, therefore, an appropriate treatment is an important aspect in recurrence prevention and remission stabilization. Since depression and drive for heroin are the key symptoms in anhedonia, we undertook the efficiency study of therapy (in anhedonia) by antidepressants belonging to the selective serotonin reuptake inhibitors (SSRI) and NMDA receptor antagonists, citalopram and memantine, respectively, which have a clinical antidepressant action and an experimental anti-addictive action. Both drugs were found to arrest effectively virtually all signs of anhedonia, however, their action on remission stabilization was rather moderate. It looked to be more promising to use, in remission stabilization, the uttermost antagonist of opiate receptors (naltrexone) blocking reliably all heroine effects. A double blind placebo-controlled study, undertaken by us, convincingly showed a significantly smaller number of relapses with naltrexone in heroin addicts. At the same time, the drug had no valuable effect on the anhedonia symptoms, which worsened the compliance entailing a poorer therapy efficiency. Finally, a combination of naltrexone (blocking the heroin action and reducing the recurrence rate) with SSRI antidepressants (effectively arresting the anhedonia symptoms and improving the compliance with naltrexone medication and remission quality) is a most promising approach to remission stabilization and recurrence prevention.
Standpoints regarding the pathomechanism of unipolar major depressive disorder (MDD) and the relevant pharmaco-therapeutical possibilities are discussed in the paper. Generations of the antidepressants from the tri- and teracyclic drugs (TCAs) to the modern, dual-acting antidepressants, including the still popular selective serotonin reuptake inhibitors (SSRIs) are surveyed in more detailed. Pharmacodynamic properties of each antidepressant subgroup with the therapeutical benefits, the occasional side-effects and with some characteristic features of the detailed ingredients in certain cases are emphasized. Some benefits and possible disadvantages regarding the combinations are also discussed briefly. The main aim of this review is to give an objective approach to the psychiatrists in order to choose the best and optimal pharmaco-therapeutical method in their daily practice.
Epidemiological studies confirm frequent appearance of pain symptoms in depressive patients and a marked prevalence of depression in pain conditions. These observations seem to point at a close intertwining between mood regulation and pain perception. In the pathogenesis of both depression and pain symptoms, an important role has been attributed to disturbances of serotonergic and noradrenergic neurotransmission as well as to neuropeptides such as opioids and substance P. In mood regulation as well as in the perception and emotional dimension of pain stimuli, such brain structures as the amygdala, anterior cingulate cortex and prefrontal cortex are of main significance. The action of antidepressant drugs results in a normalization of the activity of those neurotransmitter systems and brain structures. It was found that dual action antidepressants (i.e. influencing both serotonergic and noradrenergic system) such as tricyclic antidepressants and new generation drugs (venlafaxine, milnacipram, duloxetine, mirtazapine) exert a stronger antidepressant effect and possess a broader therapeutic spectrum, including also an effect on pain symptoms. These drugs have been also increasingly used for the treatment of pain symptoms in somatic illnesses (e.g. diabetic neuropathy, fibromyalgia).
The pregnancy is considered to be relatively high risk period for depressive episodes in women, particularly for those with pre-existing affective disorders. Epidemiological studies indicate that between 10% to 16% of pregnant women fulfil the diagnostic criteria for major depression and on average 20% is affected by an anxiety disorder. Pharmacological treatment of depression during pregnancy, however, brings with it certainties and dilemmas. It has been reported that untreated depression is associated with impaired feto-placental function, premature delivery, miscarriage, low fetal growth and perinatal unwanted effects. On the other hand, the use of antidepressant drugs in pregnancy might be at risk of major malformations (teratogenesis), neonatal toxicity, especially withdrawal symptoms and neuropsychological-behavioural impairment. In addition, the abrupt discontinuation of antidepressants, because of fear for adverse fetal effects, exposes women to serious clinical problems, in particular the disease relapse. A number of reviews indicates that among antidepressant drugs, the older SSRIs (in particular fluoxetine, sertraline, citalopram) seem to be avoided of teratogenic risks; for these reasons such drugs are nowadays considered of choice for the treatment of depression during pregnancy. Less information is available for other drugs, including triciclycs, venlafaxine, mirtazapine, bupropion, escitalopram and duloxetine. Withdrawal symptoms have been reported for all antidepressants; these symptoms, however, were self-limiting in majority of cases and had a favourable outcome. Inconclusive findings emerge, so far, from the few longitudinal studies focusing on the long-term neurodevelopment outcome in children.
Insomnia and depression are widespread diseases causing deterioration of life's quality and increasing morbidity and mortality of cardiovascular diseases. Both of them and certain antidepressants adversely affect physiological structure of sleep, while others restore it. The latter drugs must be preferred in therapy of depression accompanying insomnia, and some of them may be effective in treatment of insomnias without depression. Most antidepressants cause REM-reduction, generally with increased serotonin-function. Selective H1-antagonists readily induce sleep, and also the inhibition of cholinergic neurons in the general arousal networks promotes sleep. Sleep continuity is improved by the rise of synaptic level of serotonin. Among tricyclic antidepressants trimipramine and amitriptyline are the best to improve sleep. However, the former has low antidepressant effect and the latter has many adverse side effects. Selective serotonin reuptake inhibitors, except paroxetine, improve sleep only at the time and to the extent of restoring depression. Paroxetine has beneficial effect on sleep at the beginning of the treatment. Mirtazapine is the first-line sleep promoter among atypical antidepressants, however, its effect on increasing appetite markedly limits its application. Trazodone causes hangover, and mianserin may induce restless legs. Insomnias without depression demand lower dose of antidepressants than depression.
Sexual dysfunction is a common problem with a number of causes, including psychosocial factors, general medical illness, psychiatric disorders, and psychotropic and nonpsychiatric medications. It is especially prevalent among patients with poor emotional health and has been strongly associated with antidepressant medications. Selective serotonin reuptake inhibitors (SSRIs) in particular have demonstrated a higher incidence of sexual dysfunction than other antidepressants that work through different mechanisms of action. Further supporting the relationship between sexual dysfunction and antidepressant mechanism of action, data from a number of studies indicate that bupropion, nefazodone, and mirtazapine alleviate symptoms of sexual dysfunction and are as effective as SSRIs at controlling depressive symptoms. Although a number of strategies besides drug substitution have been utilized to help manage antidepressant-induced sexual dysfunction, many patients remain suboptimally treated; as many as 42% of patients were found to passively wait for spontaneous remission. The addition of antidotal therapy has been proven to be among the effective management strategies for sexual dysfunction. However, due to a lack of systematic data, additional studies are warranted to further investigate these findings.
Explore the source record for details and available documents.