Antidepressants for patients with tinnitus.

BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006 and previously updated in 2009.Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. It has been compared with chronic pain, and may be associated with depression or depressive symptoms which can affect quality of life and the ability to work. Antidepressant drugs have been used to treat tinnitus in patients with and without depressive symptoms. OBJECTIVES: To assess the effectiveness of antidepressants in the treatment of tinnitus and to ascertain whether any benefit is due to a direct tinnitus effect or a secondary effect due to treatment of concomitant depressive states. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; PsycINFO; CINAHL; Web of Science; BIOSIS; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 5 January 2012. SELECTION CRITERIA: Randomised controlled clinical studies of antidepressant drugs versus placebo in patients with tinnitus. DATA COLLECTION AND ANALYSIS: Two authors critically appraised the retrieved studies and extracted data independently. Where necessary we contacted study authors for further information. MAIN RESULTS: Six trials involving 610 patients were included. Trial quality was generally low. Four of the trials looked at the effect of tricyclic antidepressants on tinnitus, investigating 405 patients. One trial investigated the effect of a selective serotonin reuptake inhibitor (SSRI) in a group of 120 patients. One study investigated trazodone, an atypical antidepressant, versus placebo. Only the trial using the SSRI drug reached the highest quality standard. None of the other included trials met the highest quality standard, due to use of inadequate outcome measures, large drop-out rates or failure to separate the effects on tinnitus from the effects on symptoms of anxiety and depression. All the trials assessing tricyclic antidepressants suggested that there was a slight improvement in tinnitus but these effects may have been attributable to methodological bias. The trial that investigated the SSRI drug found no overall improvement in any of the validated outcome measures that were used in the study although there was possible benefit for a subgroup that received higher doses of the drug. This observation merits further investigation. In the trial investigating trazodone, the results showed an improvement in tinnitus intensity and in quality of life after treatment, but in neither case reached statistical significance. Reports of side effects including sedation, sexual dysfunction and dry mouth were common. AUTHORS' CONCLUSIONS: There is as yet insufficient evidence to say that antidepressant drug therapy improves tinnitus.

A novel MIP-ECL sensor based on RGO-CeO2NP/Ru(bpy)32+-chitosan for ultratrace determination of trimipramine.

A novel molecularly imprinted polymer (MIP)-electrochemiluminescence (MIP-ECL) sensor based on CeO2NP-RGO/Ru(bpy)32+-MIP-chitosan was introduced for the ultrasensitive and ultraselective detection of trimipramine (TRI). TRI-MIP was synthesized via the precipitation polymerization process. A nanocomposite of reduced graphene oxide decorated with ceria (CeO2NP-RGO) was synthesized through a facile sonochemical process. CeO2NP-RGO was utilized for modifying the surface of an electrode which consequently led to an excellent electrical conductivity, enhanced electrochemical and ECL characteristics of Ru(bpy)32+. Electrochemical and ECL behaviors of the MIP-ECL sensor were evaluated. Accordingly, the ECL intensity was significantly enhanced via TRI molecule adsorption on the MIP composite film. The prepared MIP-ECL sensor demonstrated high sensitivity and selectivity as well as good reproducibility and stability for TRI determination under the applied optimal conditions. The assays response for TRI concentration was linear in the range of 0.2-100 pM with a 0.995 correlation coefficient. The limit of detection (LOD) was as small as 0.025 pM (S/N = 3). The recoveries between 91-107% for human serum (RSDs < 4.1%) and 94-104.6% for human urine (RSDs < 3.4%) approve that the MIP-ECL sensor can be used for precise detection of TRI in complex biological matrices. Ultimately, this sensor was utilized successfully for the analysis of TRI in human serum and urine samples without any special pretreatment.

The effect of trimipramine on dream recall and dream emotions in depressive outpatients.

Trimipramine is a sedating tricyclic antidepressant which is not only effective in the treatment of depression but also in primary insomnia. In contrast to most other antidepressants, trimipramine does not affect rapid eye movement sleep. In a large sample of depressive outpatients (N = 3926), the effect of trimipramine on dream recall and dream emotions was studied. The effect of trimipramine on dream recall was small and might be explained by the reduction of negatively toned dreams. The 4-week treatment with trimipramine yielded a considerable shift in dream emotions towards the positive end of the scale, which is paralleled by the decrease of symptom severity. The present findings support the continuity hypothesis of dreaming by demonstrating a close link between waking-life symptomatolgy and negative dream emotions. Future studies should analyze dream content in order to support the hypothesis that improvement in day-time symptoms is reflected in patients' dreams.

Metabolism in adipose tissue in response to citalopram and trimipramine treatment--an in situ microdialysis study.

The intake of antidepressants is often accompanied by weight gain. Antidepressants may influence lipid and carbohydrate metabolism that can result in metabolic changes and obesity. We investigated the effect of citalopram and trimipramine on interstitial glycerol, glucose and lactate concentration and blood flow in subcutaneous adipose tissue of obese subjects by means of the microdialysis technique. In addition, the effect of stimulation with norepinephrine on metabolic response was investigated. Each subject was compared to a control subject matched for BMI and age. Each group comprised 10 subjects. Circulating plasma triglyceride concentrations were higher in drug-treated groups. In subcutaneous adipose tissue, microdialysis experiments revealed a higher and prolonged glycerol release in the presence of norepinephrine, but not under basal conditions. In citalopram treated subjects, basal glucose and lactate concentrations were higher compared with controls or with the trimipramine treated group. Local administration of norepinephrine induced a decrease in glucose levels and an increase in lactate levels, but without significant differences between groups. Local adipose tissue blood flow decreased in control groups following norepinephrine application, but remained constant in the antidepressant groups. In conclusion, citalopram and trimipramine affected glucose and lipid metabolism in adipose tissue and resulted in enhanced release of glycerol and free fatty acids into the circulation.

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system.

Preliminary reports suggested that the addition of lithium carbonate to the regimen of patients treated with, but not responding to, a tricyclic antidepressant (TCA) drug can induce a rapid alleviation of depression. We examined the effect of lithium carbonate addition in 39 patients with unipolar depression whose conditions were not improved by at least three weeks' TCA drug administration. In 30 of 42 observations, lithium carbonate brought about a greater than 50% improvement within 48 hours. In a second study, the effects of lithium carbonate addition were compared in five amitriptyline hydrochloride-pretreated and five placebo-pretreated patients who showed no improvement after a three-week treatment. All five patients receiving amitriptyline showed a greater than 50% improvement 48 hours after lithium carbonate addition, whereas only one patient in the placebo group showed a marked response. In a third study the effect of lithium carbonate withdrawal was studied in nine TCA-resistant patients who had shown a marked improvement 48 hours after lithium addition. Only five of these patients had a relapse five days after lithium discontinuation. Since animal studies have shown that TCA drugs sensitize forebrain neurons to serotonin and that lithium enhances the activity of serotonin-containing neurons, we propose that the antidepressant effect of lithium addition in TCA-resistant patients might be mediated by enhancing serotonin neurotransmission.

Tricyclic antidepressant therapy for peptic ulcer disease.

The role of tricyclic antidepressants (TCAs) as agents for treatment of peptic ulcer disease is of growing interest. In both placebo-controlled clinical trials and comparative studies with cimetidine, TCAs have proved effective and safe as ulcer-healing agents. The mechanism of action by which TCAs produce healing has not been fully elucidated. In vivo studies in man have generally shown that TCAs decrease gastric acid secretion. In addition to their well-known anticholinergic properties, in vitro studies have indicated potent H1- and H2-receptor blocking activities for these agents. Separate from these effects on acid output, the antipain/depression effect of TCAs may be of benefit in certain patients with ulcers. Other advantages of these agents include their long half-lives, low cost, and readily available serum monitoring. Further clinical studies with detailed physiologic and psychologic observations and serum monitoring using TCAs in patients with peptic ulcer disease are needed.

Pain infirmity and psychotropic drugs in oncology.

The treatment of cancer pain by psychotropic drugs is a method which has been employed for a long time [8] and in which the results obtained have appeared very interesting from the beginning: there is a high percentage of success, rapid action, absence of addiction, and although there are sometimes unpleasant side-effects, they are reversible when the treatment is stopped. Even after several years of application, this therapy still sets some unsolved problems. Some consider that psychotropics are not real analgesics, but that they work on the emotional reaction rather than on the pain itself [3]. Still others consider that the results are obtained only at the price of a state of prostration of the patient similar to that obtained after lobectomy. Finally, this procedure is reproached as having unpredictable results and indications difficult to define. We think that what has, up to now, prevented these types of problems from being solved has been the absence of a really objective evaluation of the pain in the patients observed. We have wrestled with this problem for several years [1,2], and offer the following hypothesis: what is important in considering chronic pain is, above all, the infirmity conferred upon the patient. If "pain" in the broad sense of the term lends itself to objective evaluation with difficulty, it is not the same with respect to infirmity. A method of evaluation of the physical disability intended for routine practice in a cancer center has been used on a series of 100 patients. The results obtained in this series have been analyzed and give the answer to questions such as mechanism of action, indications of psychotropic drugs and prognosis of cancer pain.

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.

Maintenance therapy for duodenal ulcer: a randomized controlled comparison of seven forms of treatment.

PURPOSE: We performed a randomized controlled trial to compare the efficacy of seven forms of maintenance treatment of duodenal ulcer, including a mealtime regimen of antacids. PATIENTS AND METHODS: We randomized 785 patients with healed duodenal ulcer to receive: (1) no treatment; (2) mealtime antacids with an acid-neutralizing capacity of 80 mmol/day; (3) an antidepressant, trimipramine 25 mg; (4) an anticholinergic, pirenzepine 50 mg; (5) cimetidine 200 mg; (6) cimetidine 400 mg; (7) ranitidine 150 mg; or (8) sucralfate 1 g twice a day. Symptomatology and side effects were assessed every 2 months and endoscopy was performed every 4 months up to 1 year. RESULTS: The patients were comparable in the majority of clinical characteristics before entry. The cumulative percentages of patients with relapse of ulcers at 12 months by life-table analysis were 61% with no treatment, 38% with mealtime antacids, 60% with trimipramine, 52% with pirenzepine, 46% with cimetidine 200 mg, 44% with cimetidine 400 mg, 30% with ranitidine 150 mg, and 40% with sucralfate. Cimetidine 400 mg, antacids, ranitidine 150 mg, and sucralfate were significantly better than no treatment and the other forms of treatment. Ranitidine was significantly better than antacids, cimetidine, and sucralfate in preventing endoscopically documented duodenal ulcer relapse by multiple comparison at 12 months, but not by life-table analysis nor when symptomatic relapses were compared. No significant difference was detected among antacids, cimetidine, and sucralfate. No major side effects occurred with the seven forms of treatment, but those receiving antacids had the highest incidence of minor adverse events (26%). CONCLUSION: This study suggests that mealtime antacids are as effective as H2-receptor antagonists and sucralfate in the maintenance treatment of duodenal ulcer disease, but have to be taken three times a day and had the highest incidence of reported minor adverse events. The relapse rate was lower with ranitidine than with cimetidine, sucralfate, and antacids, but the difference was small and may not be clinically important.

A review of trimipramine. 30 years of clinical use.

The hybrid chemical structure of trimipramine incorporates an imipramine nucleus and levomepromazine side chain. This structure predicts much of the clinical profile of trimipramine. The initial studies on trimipramine date back nearly 30 years. It now has a well-recognised clinical profile with some characteristics akin to other tricyclic antidepressants (TCA) and others which are quite distinct. It is well established as a highly effective antidepressant with an efficacy profile similar to the other TCAs. Clinically, its anxiolytic and sedative properties distinguish it from most other TCAs. Its effects on sleep architecture are unique and explain some of its unique properties. The side effect profile of trimipramine is in some ways similar to those of the tertiary amine TCAs with a preponderance of anticholinergic and sedative effects. Its cardiotoxic properties are minimal, with some findings suggesting a very favourable profile. Interactions with other drugs, psychotropic or non-psychotropic, are compatible with its pharmacological profile. These are reviewed with its clinical applications in mind. The pharmacokinetic characteristics of trimipramine differ from those of many of the other TCAs. The application of this to clinical situations is addressed. Based on experience using trimipramine, a profile of 'ideal' patient characteristics has been built up. Finally, the use of trimipramine in selected patient populations is reviewed.

Depression, circadian rhythms and trimipramine.

During depression, chronobiological disorders occur, such as disturbances in body temperature and early urinary excretion of a noradrenaline metabolite. Sleep patterns are disturbed in 90% of depressed patients; early REM sleep and shortened slow-wave sleep (stages 3 and 4), resulting in an increase in REM sleep, have been observed. Thus, an increase in REM sleep may be an indication of depression. Chronic insomnia is characterised by irregular sleep behaviour, an anxious attitude to sleep and increased cognition before sleep onset. Patients with this disorder can be divided into those with a disturbed ultradian rhythm (less than 2 REM-NREM cycles) and those with regular sleep structure (greater than 2 REM-NREM cycles). Most antidepressants reduce REM sleep, an effect evident from day 1 of administration. Trimipramine is an exception in that it has antidepressant and sedative effects without modifying REM sleep, and it possesses a different pharmacodynamic profile. Trimipramine is effective in depressed patients with chronobiological disorders such as chronic insomnia, although its mechanism of action is not fully understood.

Sleep polygraphic effects of trimipramine in depressed patients. Preliminary report.

Preliminary results are presented from an ongoing study in hospitalised depressed patients. Changes in sleep parameters were assessed on days 1 to 3 and 12 to 14 of a 4-week study in which patients received trimipramine 150 mg on day 1 and 100 mg thereafter. On days 1 to 3 and 12 to 14, 7 depressed patients had a significantly increased total sleep time and sleep efficiency index and a significantly decreased total wake time and number of intrasleep wake episodes per hour of sleep. Trimipramine treatment had no significant effect on REM sleep, percentage of REM sleep, REM duration and REM sleep stability index. However, a significant increase in REM latency was noted on days 1 to 3 but not on days 12 to 14. These polygraphic data suggest that trimipramine effects a very rapid and maintained sleep improvement in these depressed patients without significant alterations to the parameters of REM sleep.

Trimipramine, anxiety, depression and sleep.

The presence of mixed symptoms of anxiety and depression are well known to every clinician. Panic, generalised anxiety and obsessive-compulsive disorder all have considerable overlap with major depressive illness. Factor analysis of anxiety and depression symptoms has sought to predict response to treatment as well as to establish a diagnosis. Sleep disturbances are important concomitants of both syndromes. The analysis of the architecture and phasing of sleep stages has been proposed as a biological marker to separate anxiety and depression. The modification of REM and delta sleep has been correlated with antidepressant action. The earliest studies of trimipramine noted antidepressant, anxiolytic and hypnotic effects. Further observations have shown this drug to have atypical effects on REM sleep. In addition, despite its structural similarity to other tricyclic antidepressants, its pharmacological profile in animals is very different: there is no synaptosomal reuptake of serotonin or noradrenaline, and no desensitisation of beta-adrenoceptors after long term administration. A series of studies was carried out on 99 patients. Admission criteria for the studies specified a minimum score of 20 on the Anxiety Status Inventory as well as the presence of moderate depression. An uncontrolled trial demonstrated the anxiolytic efficacy of trimipramine. Further controlled trials showed superior anxiolytic efficacy of trimipramine to amitriptyline and doxepin with comparable anxiolytic efficacy of trimipramine with maprotiline. All agents had equal antidepressant effects.

Clinical originality and new biology of trimipramine.

Trimipramine differs from other antidepressant drugs in a number of ways. Although trimipramine shares equivalent efficacy with doxepin, imipramine, maprotiline and amitriptyline, as evidenced by double-blind studies, it possesses a different side-effect profile. Trimipramine is considered to be less cardiotoxic, and data presented in this paper support its minimal effect on orthostatic hypotension, as compared with clomipramine. In addition, trimipramine has less epileptogenic potential than other antidepressants such as imipramine, amitriptyline and maprotiline. Besides this different side-effect profile, trimipramine exerts differing effects on neurotransmitter functions and their reuptake. For example, trimipramine does not inhibit reuptake of noradrenaline and serotonin, and does not down-regulate beta 1-adrenoceptors. Furthermore, in common with lithium, trimipramine produces enhancement of antidepressant action in treatment-resistant depressed patients. There is evidence that trimipramine enhances the sensitivity of cortical neurons to noradrenaline after prolonged administration and may also increase the activity of serotonin neurons.

Action of trimipramine on sleep and pituitary hormone secretion.

Trimipramine is unlike other antidepressants in that it does not suppress REM sleep and possesses an atypical pharmacological profile. This antidepressant was administered in the evening to 10 depressed patients at a dosage of 75 mg on night 1 with 25 mg increments each night, up to 200 mg on night 6 and at this dosage thereafter. Sleep parameters were measured at baseline and on nights 2, 11 and 21. On nights 11 and 21, there was a significantly improved sleep pattern as shown by increases in sleep period time, total sleep time and sleep efficiency, and there was a decrease in sleep onset latency. No suppression of REM sleep occurred, and an increase was even noted; this, however, may have been due to a particularly low baseline value. Subjective assessments in which self-ratings of sleep quality were used also demonstrated an improvement in sleep. In addition, the neuroendocrine effects of trimipramine were investigated in 8 healthy volunteers after a single oral 75 mg dose. After 3 hours, a significant fall in plasma cortisol concentration from 117 to 43 micrograms/L and a significant rise in plasma prolactin concentration from 6 to 16.3 micrograms/L were observed, but there was no significant effect on plasma human growth hormone concentration. These results further support the effectiveness of trimipramine therapy in normalising a disturbed sleep pattern in depressed patients, and it may be of use in non-depressed insomniacs. The acute neuroendocrine effects of trimipramine are similar to those observed with neuroleptics and further indicate its atypical pharmacological profile.

Effects on sleep: a double-blind study comparing trimipramine to imipramine in depressed insomniac patients.

Trimipramine, a sedating tricyclic antidepressant, and imipramine were compared on polysomnographic parameters during a 4-week double-blind trial in depressed patients with insomnia and anxiety. Trimipramine eliminated objective evidence of sleep disturbance. This was not the case with imipramine, although depression improved similarly in both groups. Subjects' sleep appeared unchanged or more disturbed at the end of the treatment with imipramine. For trimipramine, the major changes in sleep parameters occurred during the first week of drug administration and did not parallel the gradual changes seen in the measures of depression. Additionally, trimipramine did not suppress REM sleep even in a subgroup of six trimipramine patients who had short rapid-eye-movement (REM) sleep latencies during the placebo baseline period, even though their depression was alleviated. The data demonstrate that (a) antidepressants may vary in their effects on sleep, even though they have similar effects on depression; (b) REM sleep suppression does not necessarily accompany improvement in depression; and (c) reports of improved sleep by patients undergoing antidepressant therapy may not reflect improvement on objective measures of sleep. The different sleep effects suggest the possibility of different antidepressant pathways.

Intravenous administration of the neuropeptide galanin has fast antidepressant efficacy and affects the sleep EEG.

OBJECTIVE: Recently, we demonstrated that the intravenous administration of the neuropeptide galanin acts on the sleep EEG of healthy young subjects similar to sleep deprivation. As this effect could imply an antidepressive potency we studied the effect of intravenous galanin administration on psychopathology and sleep EEG in patients with depression. METHODS: Galanin was administered to 10 patients with depression, who were on a stable dose of trimipramine. A placebo controlled double blind randomized design was used. Intravenous boli of galanin in a dose of 4 x 50 microg or placebo were administered hourly between 09:00 and 12:00 h. Galanin or placebo, respectively were administered on 2 days each. The sequence of the galanin or placebo days was randomized, allowing for various crossovers. The Hamilton depression rating scale score (HAMD) was performed 30 min before the first and 30 min after the last injection. The mean of the HAMD change between 08:30 and 12:30 h was chosen as primary efficacy variable. Sleep EEGs were recorded once post placebo treatment and once post verum treatment. In this case, recordings started at 23:00 h and ended at 07:00 h the next morning. RESULTS: The HAMD-difference between 08:30 and 12:30 h was significantly greater at the days of galanin-treatment compared to placebo-treatment. MANOVA revealed a significant change in sleep-EEG parameters (p < 0.05), mainly due to an increase in REM-latency (p < 0.06). CONCLUSION: The data provide preliminary evidence for an acute antidepressive efficacy of galanin, probably by a mechanism related to that of therapeutic sleep deprivation.

Combined trimipramine/phenelzine treatment of depression: case report.

Trimipramine was found safe, effective, and free of complications when used in combination with the MAOI phenelzine in the treatment of a case of refractory depression. Trimipramine co-administration with phenelzine may be an efficacious alternative pharmacotherapy for selected cases when synergistic antidepressant therapies are indicated.

Effect of tricyclic antidepressants on individual symptoms.

Improvements of individual depressive symptoms in patients with depression was compared between those treated with tricyclic antidepressants (TAD) and those treated with other psychoactive drugs or placebo. In the majority of comparisons, patients did not improve significantly more with TAD than with other drugs or placebo. These findings indicated that tricyclic antidepressants are not useful in the treatment of most patients with depression. Despite our findings, it is realized that a minority of patients with depression may benefit by treatment with tricyclic antidepressants.