zimeldine and Depressive-Disorder

The clinical pharmacology, adverse event profiles, and clinical efficacy of several serotonin reuptake inhibitors are summarized and compared with those of the classic tricyclic antidepressants. Serotonin reuptake inhibitors discussed are sertraline, zimelidine, fluoxetine, fluvoxamine, and paroxetine. While they do not differ from tricyclics in efficacy or onset of action, the serotonin reuptake inhibitors clearly have a different side effect potential. Unlike tricyclics, serotonin reuptake inhibitors provide effective antidepressant activity without sedating, anticholinergic, or cardiotoxic reactions. In comparison, tricyclics lower the seizure threshold, have anticholinergic and hypotensive effects, affect cardiac conduction, are dangerous in overdose, and may cause weight gain. The primary adverse events associated with serotonin reuptake inhibitors involve the gastrointestinal system, although side effects may be less frequent at lower dosage levels. It is important to choose antidepressant therapy on the basis of a patient's ability to tolerate the specific adverse reactions that may occur with a given agent. Although serotonin reuptake inhibitors have not replaced the tricyclics, they are a useful addition to the variety of drugs currently used for the treatment of depression.

Topics: 1-Naphthylamine; Antidepressive Agents, Tricyclic; Depressive Disorder; Fluoxetine; Humans; Paroxetine; Piperidines; Serotonin Antagonists; Sertraline; Zimeldine

The development of a new class of antidepressants that have in common their ability to inhibit the reuptake of serotonin at neuronal synapses is reviewed. There is accumulating evidence that this class of medications constitutes an advance in the management of depression; these drugs appear to be effective antidepressants with a possibly lower and more acceptable incidence of adverse reactions than the tricyclic compounds. Further exploration of these potential advantages and of the usefulness of this group of compounds for other clinical syndromes is justified.

Topics: Citalopram; Clinical Trials as Topic; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Oximes; Propylamines; Serotonin Antagonists; Zimeldine

Depression has been associated with a disturbance in serotonin function as reflected in platelet uptake of the transmitter as well as in CSF levels of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). CSF 5-HIAA levels are subnormal in approximately 30% of melancholia patients. Early studies suggested that patients with a disturbed serotonin metabolism were less responsive to treatment with uptake inhibitors with a preferential action on noradrenaline neurons. Such findings encouraged the search for compounds with a selective effect on serotonin neurons. Although some classical antidepressants are potent inhibitors of serotonin uptake, they are not selective, since their metabolites, which appear to have antidepressant effects, inhibit noradrenaline uptake. The consistent findings of an increased risk for suicide in patients with low CSF 5-HIAA underlines the importance of exploring drugs that act on serotonin transmission. The biochemical effects of some serotonin uptake inhibitors and their clinical and research potential in depression are reviewed.

Topics: 5-Hydroxytryptophan; Alanine; Citalopram; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Imipramine; Oximes; Paroxetine; Piperidines; Propylamines; Serotonin; Serotonin Antagonists; Trazodone; Zimeldine

The effects of acute and chronic antidepressant treatment on various aspects of 5-HT neurotransmission are reviewed, in order to assess the net effect of antidepressants on transmission across 5-HT synapses. Events considered include presynaptic effects of antidepressants (on autoreceptor function, uptake and turnover) and effects on postsynaptic receptor function (assessed by electrophysiological, neuroendocrine, behavioural, and receptor binding methods). Acute antidepressant treatment has variable effects: transmission may be enhanced, unchanged or reduced, depending mainly upon the relative contributions of 5-HT uptake blockade and 5-HT receptor antagonism. However, on chronic administration, most antidepressants appear to enhance 5-HT transmission. This effect is clearest in the case of ECS, which has little effect on 5-HT turnover, but reduces uptake and increases postsynaptic receptor function. MAOIs may be an exception: there is little evidence that MAOIs enhance 5-HT transmission following chronic treatment. Most other antidepressant drugs, including some which are powerful receptor antagonists on acute administration, reduce 5-HT receptor function briefly, but enhance receptor function if several hours elapse between the final injection and testing. Zimelidine has little effect on postsynaptic receptor function, but enhances 5-HT transmission by its powerful blockade of 5-HT uptake. Chronic treatment with antidepressant drugs has usually been found to reduce binding to 5-HT2 receptors; it is difficult to reconcile these observations with the functional studies. In general, with the possible exception of MAOIs, chronic administration of antidepressants may enhance 5-HT transmission by both pre- and post-synaptic effects, and the relative contributions vary. This conclusion supports the classical "indoleamine hypothesis of depression" rather than the more recent "hypersensitive serotonin receptor" theory.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Depressive Disorder; Disease Models, Animal; Electroshock; Humans; Hydroxyindoleacetic Acid; Hypothalamo-Hypophyseal System; Monoamine Oxidase Inhibitors; Olfactory Bulb; Pituitary-Adrenal System; Rats; Receptors, Serotonin; Serotonin; Synaptic Transmission; Zimeldine

Topics: Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Electroconvulsive Therapy; Hippocampus; Humans; Lithium; Norepinephrine; Rats; Receptors, Adrenergic, alpha; Serotonin; Synaptic Transmission; Zimeldine

Topics: Albuterol; Animals; Antidepressive Agents; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Dibenzocycloheptenes; Drug Evaluation, Preclinical; Fluoxetine; History, 20th Century; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Psychopharmacology; Receptors, Adrenergic; Receptors, Serotonin; Trazodone; Zimeldine

Topics: Alprazolam; Antidepressive Agents; Antidepressive Agents, Tricyclic; Benzodiazepines; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Fluoxetine; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Zimeldine

Zimelidine is a new antidepressant, which is structurally unrelated to the tricyclic and tetracyclic antidepressants. The pharmacological profile of zimelidine is different to that of other antidepressants in that it appears to owe the major part of its activity to the inhibition of serotonin uptake within the central nervous system. It appears that the demethylated metabolite, norzimelidine, may be responsible for most of the pharmacological activity. Studies to date suggest that zimelidine has overall efficacy comparable with that of amitriptyline, desipramine, maprotiline and doxepin in depressive illness, but at dosages which have achieved a similar overall clinical improvement zimelidine does not cause sedation, and anticholinergic side effects are mild and occur infrequently. Preliminary evidence suggests that zimelidine is effective against concomitant anxiety in depressed patients, and that it may also be useful in treating phobic anxiety. Zimelidine appears less likely to cause serious cardiotoxicity, in therapeutic dosages or an overdosage, than the tricyclic antidepressants, but it has not been studied in patients with cardiovascular disease. Sleep disturbance has occurred significantly more frequently during zimelidine therapy than during therapy with other sedative antidepressants, but whether this simply reflects the absence of sedation with zimelidine, or an effect on sleep as such, is presently unclear. Zimelidine appears to be effective and well tolerated in elderly patients. Thus, some aspects of the drug's profile (e.g. apparent low incidence of anticholinergic effects or drowsiness) may offer potential advantages in some patients; however, clinical experience with zimelidine to date has been limited, and further well designed studies are required to define the role of the drug more clearly in treating depressive illness compared with other antidepressants, and particularly to define whether some types of depression may respond more readily to zimelidine than to other antidepressants.

Topics: Antidepressive Agents; Body Weight; Brompheniramine; Central Nervous System; Depressive Disorder; Drug Interactions; Endocrine Glands; Hemodynamics; Humans; Kinetics; Parasympatholytics; Pyridines; Zimeldine

Body weight change was monitored in 73 hospitalized depressed patients treated with one of four antidepressants for 1 month. After a 2-week medication-free period, patients were randomly assigned to treatment with amitriptyline, nortriptyline, desipramine, or zimelidine. By the end of 1 month, treatment with all three tricyclic compounds promoted weight gain, with the greatest increase observed during amitriptyline treatment; less weight was gained by patients treated with nortriptyline and desipramine. In contrast, most patients treated with zimelidine showed no weight gain and, in many cases, demonstrated weight loss. Weight change during treatment was not associated with age, sex, severity of depression, obesity, weight loss during depression, or clinical response.

Topics: Adult; Amitriptyline; Antidepressive Agents; Depressive Disorder; Desipramine; Female; Humans; Male; Middle Aged; Nortriptyline; Weight Gain; Zimeldine

The effects of four antidepressant treatments on platelet tritiated imipramine binding have been studied in 51 hospitalized patients with severe major depressive disorder. There was an increase in maximum binding (Bmax) during the first week of treatment with antidepressants and electroconvulsive therapy, which was further magnified after three weeks' treatment with the serotonin uptake blockers alaproclate and zimeldine hydrochloride, but the Bmax values returned to baseline levels with nortriptyline hydrochloride and electroconvulsive therapy. The equilibrium dissociation affinity constant (Kd) did not change with any of the treatments. On reexamination one or two years after admission to the study, Bmax had not reached control values in clinically recovered, drug-free patients. Low pretreatment Bmax was associated with delusions during illness and with a poor long-term clinical outcome. There was no correlation between binding parameters and monoamine metabolite concentrations in the cerebrospinal fluid, either before or during treatment.

Topics: Adult; Aged; Alanine; Antidepressive Agents; Blood Platelets; Carrier Proteins; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Imipramine; Male; Middle Aged; Nortriptyline; Outcome and Process Assessment, Health Care; Psychiatric Status Rating Scales; Receptors, Drug; Receptors, Neurotransmitter; Receptors, Serotonin; Zimeldine

The development of a new class of antidepressants that have in common their ability to inhibit the reuptake of serotonin at neuronal synapses is reviewed. There is accumulating evidence that this class of medications constitutes an advance in the management of depression; these drugs appear to be effective antidepressants with a possibly lower and more acceptable incidence of adverse reactions than the tricyclic compounds. Further exploration of these potential advantages and of the usefulness of this group of compounds for other clinical syndromes is justified.

Topics: Citalopram; Clinical Trials as Topic; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Oximes; Propylamines; Serotonin Antagonists; Zimeldine

Seventy-five outpatients with major depressive disorder (RDC) were randomly referred to treatment with a dominant serotonin (5-HT) reuptake blocker (zimeldine, 100 mg, b.i.d. n = 40) or a dominant noradrenaline (NA) reuptake blocker (maprotiline, 75 mg, b.i.d. n = 35). Seven patients on each drug were non-responders after up to 4 weeks of treatment and were after a washout week crossed over to the other drug for up to another 8 weeks of treatment. There was a significant and similar improvement after 4 weeks of treatment with the second drug. After up to 8 weeks of treatment all patients but one in each group were much improved with the second drug. The existence of two biochemical subgroups of depression is discussed.

Topics: Adult; Animals; Anthracenes; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Hypothalamus; Male; Maprotiline; Middle Aged; Norepinephrine; Rats; Receptors, Adrenergic; Receptors, Serotonin; Serotonin; Synaptosomes; Zimeldine

Seventy-five outpatients with major depressive disorder (RDC) were randomly referred to treatment with a dominant 5-HT reuptake blocker (zimeldine, 100 mg b.i.d.) or a dominant NA reuptake blocker (maprotiline 75 mg b.i.d.). Pretreatment biochemical, pharmacodynamic and pharmacokinetic variables were studied and related to the treatment outcome with the two drugs. Female responders to the dominant 5-HT reuptake blocker were characterized by low pretreatment accumulation of 14C-5-HT in rat synaptosomes, when incubated in patient plasma. Among zimeldine responders there was a relationship between antidepressive effect and steady-state concentrations of zimeldine and norzimeldine. These findings support the hypothesis of a subgroup of depression characterized by serotonin disturbance.

Topics: Animals; Anthracenes; Depressive Disorder; Female; Humans; Hypothalamus; Male; Maprotiline; Norepinephrine; Rats; Serotonin; Sex Factors; Synaptosomes; Zimeldine

Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pain; Personality Tests; Psychophysiologic Disorders; Random Allocation; Sick Role; Zimeldine

We performed a randomized, double-blind clinical trial comparing the efficacy and safety of zimelidine with amitriptyline and placebo in outpatients with major depression, in particular patients with mixed anxiety/depressive symptomatology. Overall, amitriptyline was more effective than zimelidine and placebo after 4 weeks of treatment. However, when those patients with more severe depression were specifically examined, both antidepressants were equal in efficacy and superior to placebo. We also found no evidence for a greater likelihood of a zimelidine-induced peripheral neuropathy in this study. The present results suggest that zimelidine may be more effective in the treatment of severely depressed patients, rather than those with more mild mixed anxiety/depressive syndromes.

Topics: Adult; Amitriptyline; Anxiety; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Zimeldine

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.

Topics: Adolescent; Adult; Aged; Bipolar Disorder; Clorgyline; Depressive Disorder; Desipramine; Female; Glycols; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Propylamines; Serotonin; Zimeldine

Seventy-five outpatients with major depressive disorder (RDC) were randomly referred to treatment with a dominant serotonin (5-HT) uptake inhibiting drug (zimeldine, 100 mg b.i.d.) or a dominant noradrenaline (NA) uptake inhibiting drug, (maprotiline, 75 mg b.i.d.). The total antidepressive effect was similar in the two groups for up to 4 weeks of treatment. Both drugs gave an effect on the depressive syndrome as a whole, with no preference for mood, anxiety, retardation or vital symptoms. Good response to the NA drug correlated to few prior episodes and few years since first episode, whereas the 5-HT drug had its best effect when there were several previous episodes.

Topics: Adult; Anthracenes; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Maprotiline; Middle Aged; Norepinephrine; Recurrence; Time Factors; Zimeldine

The Montgomery and Asberg Depression Rating Scale (MADRS) is a 10 item severity scale constructed to be sensitive to change with treatment. It was designed to be sensitive for individual items and is therefore useful for measuring differential profiles of action. The MADRS profiles of activity were examined in a six-week double-blind comparative group study of depressed patients treated with mianserin or zimeldine. Three of the ten items on the MADRS showed individual significant advantages for mianserin, reduced sleep (weeks 1 and 3), concentration difficulties (week 1), and reduced appetite (week 3). These findings are in agreement with earlier reports of poor sleep and gastrointestinal upset associated with the 5-HT uptake inhibitor zimeldine. The selective improvement in concentration difficulties and in the other items support the view that mianserin is particularly useful in alleviating the anxiety associated with depression. The sedative effect of mianserin did not appear to interfere with concentration. There were significant improvements in the mianserin-treated group at 1, 2, 3, and 4 weeks for the MADRS, Hamilton Depression Rating Scale and Clinicians Global Impression scale. There was no significant advantage for mianserin at 5 and 6 weeks. The differential clinical effects were apparent early in the study but any selectivity of action appeared to be overwhelmed by the general antidepressant effect later in treatment.

Topics: Adult; Aged; Antidepressive Agents; Depressive Disorder; Dibenzazepines; Drug Evaluation; Female; Humans; Male; Mianserin; Middle Aged; Psychiatric Status Rating Scales; Zimeldine

"New generation" antidepressants are generally considered to include all agents introduced in recent years which are neither tricyclic in structure nor monoamine oxidase inhibitors. They include the tetracyclics (mianserin and maprotiline), the bicyclic serotonergic compounds (fluoxetine and citalopram), and the unicyclics (bupropion), as well as the triazolobenzodiazepine derivatives (alprazolam), the triazolopyridines (trazodone) and the tetrahydroisoquinolines (nomifensine). Methodologic and economic considerations have hampered attempts to develop agents with significantly greater specificity or safety than traditional agents. Traditional agents, while lacking specificity, do have extensive records of efficacy and long-term safety and are usually less expensive than new agents. Patients not responding to traditional agents often have medical or characterologic problems that exclude them from participating in controlled studies of new agents. These problems are discussed and potential approaches to the development of new agents are presented.

Topics: Alprazolam; Antidepressive Agents; Benzodiazepines; Bupropion; Citalopram; Clinical Trials as Topic; Depressive Disorder; Dopamine; Drug Evaluation; Fluoxetine; Humans; Maprotiline; Nomifensine; Norepinephrine; Propiophenones; Propylamines; Receptors, Neurotransmitter; Serotonin; Trazodone; Zimeldine

Forty-five patients suffering from a major depression were administered zimeldine, amitriptyline or placebo (15 patients in each group) in a double-blind controlled study. In the zimeldine group, seven of the 14 patients treated for more than one week presented a toxic syndrome consisting in a severe prostration, fever, myalgias and arthralgias. In all patients presenting this syndrome, laboratory analyses revealed an elevation of alkaline phosphatase and of aspartate and alanine aminotransferases and a decrease in white blood cell and platelet counts. Three patients presented a mild proteinuria and hematuria. Although an immunological mechanism cannot be ruled out, several characteristics of this reaction suggest the formation of a metabolite of zimeldine with direct cellular toxicity. The relatively high starting dose of 200 mg/day of zimeldine administered in the present study and the increment to 300 mg/day after only seven days might have contributed to the high incidence of toxic reactions observed.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Depressive Disorder; Female; Humans; Leukocyte Count; Male; Middle Aged; Platelet Count; Time Factors; Zimeldine

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

Topics: Adolescent; Adult; Aged; Brain; Clinical Trials as Topic; Depressive Disorder; Desipramine; Double-Blind Method; Female; Growth Hormone; Humans; Hydrocortisone; Luteinizing Hormone; Male; Middle Aged; Prolactin; Receptors, Adrenergic; Receptors, Serotonin; Zimeldine

The 24-hour urinary serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) outputs were repeatedly measured in 21 patients with major affective disorders after a minimum of three weeks free of drug treatments and at steady state during subsequent antidepressant treatments or during the second week after a series of electroconvulsive treatments (ECTs). The 5-HIAA outputs were more variable over time than the outputs of major catecholamine metabolites, previously studied by us. Patients with rapid mood cycles excreted large amounts of 5-HT. Lithium carbonate and ECTs reduced the outputs of 5-HT and 5-HIAA, respectively. Lithium carbonate also stabilized the output of 5-HT. No common effect of different antidepressant treatments on indole outputs was found.

Topics: Antidepressive Agents; Clorgyline; Depressive Disorder; Desipramine; Electroconvulsive Therapy; Female; Humans; Hydroxyindoleacetic Acid; Lithium; Lithium Carbonate; Male; Middle Aged; Placebos; Serotonin; Zimeldine

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Desipramine; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Zimeldine

A quantitative method for measuring serotonin uptake inhibition in fresh platelets incubated in diluted plasma (stored frozen until analyzed) from patients treated with tricyclic and related antidepressants is described. The method was used in a clinical trial comparing the specific serotonin uptake inhibitor zimelidine with the mixed serotonin-norepinephrine uptake inhibitor desipramine in patients with endogenous depression, and correlating this with plasma drug concentration assessment. The bioassay, based on the use of one single, low concentration of serotonin, was found to be very sensitive and to have a high reliability (coefficient of variation about 2% as calculated from duplicate samples), and to correlate highly with log plasma concentration of zimelidine, norzimelidine, and of desipramine. This bioassay may have some advantages in relation to plasma drug concentration assessment, but only future studies can show whether it provides a better basis for antidepressant drug monitoring.

Topics: Adult; Aged; Blood Platelets; Depressive Disorder; Desipramine; Female; Humans; Kinetics; Male; Middle Aged; Serotonin; Zimeldine

In a double-blind comparison of 21 inpatients with endogenous depression 225 mg zimeldine demonstrated the same degree of antidepressive efficacy as 150 mg amitriptyline after 4 weeks of treatment. Only "sleep disturbances" on the Hamilton Rating Scale for Depression (HRS) showed significant (P less than 0.05) improvement with amitriptyline. Only small differences in the frequency of side effects were seen. In the zimeldine group, increased sweating and headache were more pronounced, while the amitriptyline patients more often reported dry mouth and constipation. Body weight was not significantly changed by either treatment. In the zimeldine group, treatment had to be interrupted in three patients due to hypersensitivity reactions in the form of drug fever. Three other patients in the zimeldine group showed clinically significant elevation of liver enzymes. Hypersensitivity reactions and abnormal blood chemistry were both reversible. The adverse reactions are discussed, the cause of the occurrence remaining unknown.

Topics: Adult; Amitriptyline; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Psychiatric Status Rating Scales; Zimeldine

Thirty-nine (39) patients entered a double blind study conducted to compare the therapeutic efficacy and safety of Zimelidine and amitriptyline in endogenous depression. Following a 3-5 day washout period, patients were randomly allocated to Zimelidine or amitriptyline for 6 weeks period and were assessed regularly. 63% of Zimelidine and 65% of amitriptyline patients showed significant clinical improvement. Side effects recorded with amitriptyline were predominantly anticholinergic and headaches with Zimelidine. It is concluded that while Zimelidine and amitriptyline show equally efficacous antidepressant properties, zimelidine may offer a slight therapeutic advantage due to lack of anticholinergic side-effects.

Topics: Adult; Aged; Amitriptyline; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Zimeldine

The effects of amitriptyline (n = 14) or zimelidine (n = 13) on the sleep electroencephalogram of hospitalized depressed patients were assessed in a double-blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings, and lighter non-rapid eye movement (REM) sleep than before taking the drug. Zimelidine did, however, induce a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first two nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM-suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these two drugs.

Topics: Adult; Amitriptyline; Depressive Disorder; Electroencephalography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Sleep; Sleep, REM; Zimeldine

A double-blind comparison of zimeldine, a selective 5-HT reuptake inhibitor, and nomifensine, a noradrenaline and a dopamine reuptake inhibitor, was carried out in 43 inpatients with a scheduled treatment period of 6 weeks. All patients were diagnosed as definite major depressive disorder according to Research Diagnostic Criteria (RDC), and the WHO International Classification of Diseases (ICD-9). The antidepressive efficacy was evaluated by a 10-item subscale of the Comprehensive Psychopathological Rating Scale (CPRS), a clinical global impression (CGI) scale and a self-rating scale (VAMS). Side effects were recorded, and anticholinergic effect was evaluated by parotid saliva volume measurement. No statistically significant differences in efficacy or profile between the two drugs were demonstrable. With the exception of increased sweating in the zimeldine group there were no statistically significant differences in side effects.

Topics: Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Isoquinolines; Nomifensine; Psychiatric Status Rating Scales; Psychotic Disorders; Zimeldine

Topics: Albuterol; Animals; Antidepressive Agents; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Dibenzocycloheptenes; Drug Evaluation, Preclinical; Fluoxetine; History, 20th Century; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Psychopharmacology; Receptors, Adrenergic; Receptors, Serotonin; Trazodone; Zimeldine

Topics: Alprazolam; Antidepressive Agents; Antidepressive Agents, Tricyclic; Benzodiazepines; Brompheniramine; Bupropion; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Fluoxetine; Humans; Monoamine Oxidase Inhibitors; Propiophenones; Zimeldine

Twenty-eight hospital inpatients with a primary major depressive disorder were treated with either zimelidine or placebo. Patients were matched for age, sex, and initial severity of depression and assigned double blind to the treatment regimen. An initial dosage of 150 mg/day was used for up to 6 weeks. Zimelidine was significantly more effective in alleviating the symptoms of depression than placebo, with 82% of zimelidine and 25% of placebo patients showing clinical improvement. There were few complaints of severe side effects in zimelidine-treated patients, and few effects on the cardiovascular system. Two zimelidine-treated patients were withdrawn for suspected drug-related adverse events. Zimelidine was a safe, effective antidepressant in this group of patients.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Blood Pressure; Brompheniramine; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Heart Rate; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

This paper presents the results from a large multicenter study, performed at three clinical research units in the USA. Prior to a three to seven days of placebo washout period, patients were randomly assigned to zimelidine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. The scheduled treatment period was four weeks. Dosage range was 75-300 mg/day for active medications. The rating instruments were the Hamilton Depression Scale and the Clinical Global Impression scale. The side effects were recorded by using a side effect inventory (TESS). Vital signs, laboratory work including clinical chemistry, ECG, and plasma levels of drugs, were performed. In the main efficacy evaluation there were 229 depressed outpatients included, all having completed at least two weeks of treatment after the washout period. The patients treated with zimelidine as well as those treated with amitriptyline showed a significant improvement relative to the placebo treated patients. For the safety evaluation 263 patients were included. Side effects, in particular anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimelidine group as compared to the amitriptyline group. Only marginal differences regarding side effects were reported for zimelidine compared to those reported for placebo.

Topics: Adolescent; Adult; Aged; Amitriptyline; Antidepressive Agents; Brompheniramine; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

Zimelidine, a specific 5HT uptake inhibitor (final dose 225 mg), and desipramine, mainly a noradrenaline uptake inhibitor (final dose 150 mg), were given in random order to 24 in- and out-patients fulfilling the Research Diagnostic Criteria for Major Depressive Disorder, definite or probable endogenous type, for a 3-week treatment period. Nonresponders were crossed over to the other drug for another 3 weeks. There was a nonsignificant trend towards more overall improvement on desipramine. Some patients in both groups showed very little change during 3 weeks, indicating a bimodal distribution of response to either drug. Several nonresponders improved markedly upon direct crossing over to the other drug. There were few and mild side effects on both drugs, with no significant difference between them. No significant correlation was found between improvement and plasma concentrations of zimelidine, norzimelidine, or desipramine, whereas a significant positive correlation was found between improvement and platelet serotonin uptake inhibition (measured in fresh platelets incubated in diluted plasma from the patients) in zimelidine-treated patients.

Topics: Adolescent; Adult; Aged; Brompheniramine; Depressive Disorder; Desipramine; Double-Blind Method; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Serotonin; Zimeldine

Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adult; Antidepressive Agents; Bipolar Disorder; Brompheniramine; Clorgyline; Depressive Disorder; Desipramine; Dopamine; Electroconvulsive Therapy; Female; Homovanillic Acid; Humans; Male; Middle Aged; Zimeldine

Zimeldine tolerability was compared to amitriptyline and placebo in a large multicentre study performed at three clinical research units in the U.S.A. Prior to a placebo washout period of 3-7 days, patients were randomly assigned to zimeldine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. Dosage range was 75-300 mg/day for active medications, and the scheduled treatment period was 4 weeks. The side-effects were recorded by using a Treatment Emergent Symptom Scale (TESS). Vital signs were monitored and laboratory investigations, including chemistry and drug plasma levels, were performed. Two hundred and sixty-three patients were included in the safety evaluation. Side-effects, particularly anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimeldine group compared to the amitriptyline group. Only marginal differences in side-effects were reported between zimeldine and placebo. Significantly more patients receiving amitriptyline were withdrawn from treatment as a result of adverse effects. Thus, zimeldine appears to be an effective antidepressant with marked advantages with regard to tolerability. It is therefore an important new contribution to the treatment of depressive disorders.

Topics: Adult; Aged; Amitriptyline; Blood Pressure; Body Weight; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Drug Tolerance; Female; Humans; Male; Middle Aged; Placebos; Sweating; Zimeldine

The efficacy of zimeldine in preventing depressive episodes in recurrent major depressive disorders was evaluated in a randomized, placebo-controlled study involving 40 patients. The intended study period was 18 months. The results showed zimeldine to be significantly more effective than placebo, both in terms of preventing recurrence (t-test: P less than 0.001) and the withdrawal rate (Cox's test: P less than 0.01). Adverse symptoms for zimeldine did not differ from placebo. There were no noteworthy changes in clinical chemistry, blood pressure, ECG and pulse rate.

Topics: Adult; Aged; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Compliance; Recurrence; Zimeldine

Two studies of zimeldine in depressive illness are reported, one a double-blind, placebo-controlled trial, the other an open evaluation. In both studies, zimeldine was shown to have antidepressant properties. No simple relationship between plasma zimeldine or norzimeldine and clinical effect was demonstrated in eight patients treated for 6 weeks. Minor changes in electrocardiographic parameters were noted in some zimeldine patients. Side-effects attributable to zimeldine treatment were generally of mild to moderate severity and the drug was well tolerated. During the studies, one patient overdosed on zimeldine (5.2 g) and, although plasma concentrations were excessive, minimum side-effects were recorded. Two cases of suspected adverse drug reactions with zimeldine are described.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Zimeldine

Zimeldine, a new antidepressant with a selective inhibition of 5-HT reuptake, was compared with imipramine in a double-blind comparative study. The trial was conducted on 95 patients with primary major depressive disorder, of endogenous character. During the 4-week study period clinical efficacy was evaluated by using the Hamilton Depression (HAM-D) scale, Beck's Inventory and global ratings. Zimeldine (100 mg b.d.) was shown to have as good an antidepressive effect as imipramine (50 mg t.d.s.) when evaluated on the HAM-D scale. Assessment of the symptom improvement on this rating scale suggested that zimeldine was more effective in improving the patient's insight of the disease. There was no significant difference between zimeldine and imipramine as assessed by a final global improvement rating scale as well as by the patient's own impression. Exploratory data analysis revealed that zimeldine was significantly more effective than imipramine in the following groups; patients over 40 years of age; patients whose initial onset of illness occurred at over 40 years; patients with a history of at least three episodes of depressive illness; patients with mild to moderate depression; and patients who had previously failed to show an appreciable response to other antidepressant treatment. Analysis of global safety ratings revealed that zimeldine is significantly safer than imipramine, with a lower incidence of adverse symptoms involving the autonomic nervous system, especially anticholinergic reactions. No significant difference was observed between the two groups with respect to abnormal laboratory reports. One zimeldine patient developed symptoms suggesting a hypersensitivity reaction (fever, skin eruption and elevation of plasma levels of transaminases), which led to the patient's withdrawal from drug treatment.

Topics: Adolescent; Adult; Age Factors; Aged; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Psychiatric Status Rating Scales; Serotonin; Zimeldine

The similarities and differences in the clinical response and incidence of adverse symptoms between zimeldine and amitriptyline have been evaluated by use of a combined analysis of four double-blind clinical trials in depression. In total, 197 patients were included in this series of studies. The efficacy of the drugs was assessed using the Hamilton Rating Scale for Depression (HAM-D). Reports of adverse symptoms were actively elicited by use of a check-list of symptoms and rated for severity. The overall clinical efficacy of the two drugs was shown to be equivalent with a high degree of statistical confidence. However, there exist differences in the profile of action. Amitriptyline has a significant advantage in insomnia problems. In spite of this zimeldine was shown to be at least as effective as amitriptyline in reducing anxiety. Amitriptyline is associated with significantly more anticholinergic side-effects, whereas headache is more disturbing during zimeldine treatment. The combination of several independent trials based on similar protocols can be a useful tool to increase the statistical reliability of conclusions relative to that which can be achieved in standard sized, individual studies in depression.

Topics: Adult; Amitriptyline; Anxiety; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Headache; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Sleep Wake Disorders; Zimeldine

Zimeldine, imipramine and placebo were studied in a randomized, double-blind, parallel group comparison of 119 patients with primary affective disorders. These out-patients were between 18 and 65 years of age and all received placebo single-blind during an initial 3-7-day washout period. During the subsequent 6-week double-blind period, patients were titrated from 50 mg b.d. to 150 mg b.d. with zimeldine, a potent and selective inhibitor of 5-HT reuptake, with imipramine, an inhibitor of noradrenaline and 5-HT reuptake, or with a corresponding number of placebo capsules. The zimeldine treatment group had significantly lower mean HAM-D scale total scores than the placebo and imipramine groups at week 4 and last available assessment. There was a significantly greater proportion of patients showing an improvement of 50% or more in HAM-D score, among the zimeldine group than in the placebo group at week 4, and among the imipramine group at weeks 4, 6 and last available assessment. The Clinical Global Impression (CGI) scales and the 56-item Hopkins Symptom Check-list (HSCL-56) self-rating inventory both showed significantly more improvement in the zimeldine patients than in the placebo or the imipramine patients. Fewer zimeldine patients reported adverse experiences than imipramine patients. Dry mouth was the most frequently reported adverse experience, occurring significantly more often in the imipramine group than the zimeldine or the placebo groups; significantly more zimeldine than placebo patients reported dry mouth. Headache was the only other adverse experience which occurred more often in the zimeldine than in the placebo group. The imipramine group had consistently higher mean pulse rates than the other two groups, and postural hypotension was also more common in the imipramine group.

Topics: Adolescent; Adult; Aged; Bipolar Disorder; Blood Pressure; Body Weight; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Headache; Humans; Imipramine; Middle Aged; Placebos; Psychiatric Status Rating Scales; Pulse; Zimeldine

The safety and efficacy of zimeldine--the 5-HT reuptake blocker--was investigated in a 3-week open surveillance study of 15,000 out-patients with depressive illness. In general, a single daily dose of 200 mg of zimeldine was given to adults for a minimum of 3 weeks. Patients of 65 years or over received 100 mg. The drug was well tolerated and troublesome side-effects occurred in only a small percentage of patients. No previously unencountered side-effects or new pattern of side-effects emerged from this study. The general impression of the efficacy of zimeldine confirmed previous findings (i.e. that zimeldine is an effective antidepressant).

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Family Practice; Female; Germany, West; Humans; Male; Middle Aged; Zimeldine

13 patients with endogenous depression, who had failed to obtain a lasting response to other antidepressant drugs or to electroconvulsive therapy, were treated with zimelidine. 3 showed a marked, and 3 a mild improvement. Side effects were minimal.

Topics: Aged; Antidepressive Agents; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Female; Headache; Humans; Male; Middle Aged; Personality Inventory; Pyridines; Zimeldine

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Pyridines; Trazodone; Zimeldine

Topics: Adult; Amitriptyline; Antidepressive Agents; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Pyridines; Zimeldine

The authors conducted a double-blind, placebo-controlled clinical trial of the selective 5-HT reuptake inhibitor zimelidine in the treatment of major depressive illness. Zimelidine had the same antidepressant efficacy as amitriptyline but significantly fewer side effects, especially anticholinergic effects.

Topics: Adolescent; Adult; Aged; Amitriptyline; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Placebos; Pyridines; Serotonin Antagonists; Zimeldine

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.

Topics: Antidepressive Agents; Brain; Brompheniramine; Depressive Disorder; Desipramine; Female; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Normetanephrine; Pyridines; Vanilmandelic Acid; Zimeldine

A double-blind, randomized clinical study was conducted in thirty-four out-patients suffering from major depressive disorders comparing zimelidine with amitriptyline. The dosage was flexible, maintenance doses varying between 50-150 mg in the amitriptyline group and 50-300 mg in the zimelidine group. After a wash-out period of at least a week the mean score in Hamilton Rating Scale for depression (HRS) was 22.2 for zimelidine and 21.9 for amitriptyline. During the treatment period of 6 weeks, zimelidine and amitriptyline appeared to be equally effective as antidepressants in HRS and Global Ratings. The zimelidine group showed significantly less somnolence and dry mouth. No clinically important changes were seen in the laboratory parameters during the study.

Topics: Adult; Ambulatory Care; Amitriptyline; Antidepressive Agents; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

A comparative evaluation of zimelidine, a potent and selective serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, was carried out in a 4-week randomized, double-blind study in 65 hospitalized patients with endogenous depression. For evaluation of the clinical effect, Hamilton Rating Scale for depression (HRS) and a 14-item scale chosen from the Comprehensive Psychopathological Rating Scale (CPRS) were used. The concentration of drug in plasma was determined on the same days as the clinical ratings. There were no significant difference in the overall therapeutic effect between the two drugs. However, zimelidine had significantly better effect on anxiety. Although both agents were well tolerated, the zimelidine-treated patients reported significantly less severe anticholinergic side effects. Body weight did not change significantly in either treatment group. In the total material ther were no significant correlation between plasma concentrations of zimelidine, norzimelidine and desipramine and the amelioration score of either HRS and CPRS.

Topics: Adult; Aged; Antidepressive Agents; Bipolar Disorder; Brompheniramine; Depressive Disorder; Desipramine; Double-Blind Method; Female; Humans; Male; Middle Aged; Norepinephrine; Psychiatric Status Rating Scales; Pyridines; Serotonin; Zimeldine

Depressed patients, who did not respond after 4 weeks treatment with zimelidine 100 mg b.i.d. (five patients) or desipramine 75 mg b.i.d. (11 patients) in a double-blind randomized study were crossed over, after 1 placebo week, to 4 weeks of treatment with the other drug. The three zimelidine non-responders who responded to desipramine were significantly more retarded compared with eight desipramine non-responders who responded to zimelidine. It was observed that two patients with bipolar depression developed mania during crossover treatment with desipramine, while two patients with bipolar depression who were treated with zimelidine during the second treatment period did not show any symptoms of mania. Three patients who were non-responders during both treatment periods had lower plasma concentration of the drugs compared with respective responding groups.

Topics: Antidepressive Agents; Bipolar Disorder; Brompheniramine; Depressive Disorder; Desipramine; Double-Blind Method; Female; Humans; Male; Middle Aged; Norepinephrine; Pyridines; Serotonin; Zimeldine

Topics: Adolescent; Adult; Aged; Amitriptyline; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Female; Humans; Male; Middle Aged; Pyridines; Sleep Initiation and Maintenance Disorders; Zimeldine

Outpatients with endogenous depression diagnosed according to the research diagnostic criteria of Feighner et al. were randomly referred to treatment with zimelidine (100 mg b.i.d., group Z) or maprotiline (75 mg b.i.d., group M). Patients who did not respond to treatment by days 28 were crossed over to the other drug. This preliminary report comprises results up to day 28 and includes antidepressive effect as rated by CPRS and globally, side effects, clinical chemistry and ECG. Ratings were double-blind at days 0, 7, 14 and 28, and a washout period of 4--7 days preceeded the trial. Group Z includes 27 and group M 28 patients with equal distribution of sex, age, duration of present episode, initial severity, etiology and previous course. There were 11 dropouts in group M and 5 in group Z due to side effects or treatment failure. On the other hand, 8 patients in group Z had to cross over to the other drug versus 2 in group M. According to the total CPRS score and the global score the antidepressive effect was somewhat better in group Z at 2 weeks but similar at 1 and 4 weeks. Group Z is less sedative but still seems to have a better anti-anxiety effect. Side effects were on a low level. There was a greater number of patients in group Z who complained of nausea, vomiting, loose stools, sleep disorder and sweating, and in group M dry mouth, drowsiness, dizziness and accomodation difficulties. Chemical analyses and ECG showed slight and inconsistent changes.

Topics: Adult; Aged; Anthracenes; Antidepressive Agents; Brompheniramine; Depression; Depressive Disorder; Electrocardiography; Female; Humans; Male; Maprotiline; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

A double-blind comparison of zimelidine, a potent and fairly selective 5-hydroxytryptamine (5-HT) uptake inhibitor, and desipramine, a noradrenaline (NA) uptake inhibitor, was carried out in hospitalized patients with endogenous depression. The patients were randomized into parallel groups receiving either zimelidine 100 mg b.i.d. or desipramine 75 mg b.i.d. Forty patients completed the study, twenty in each treatment group. Patients who did not respond adequately to one drug after 4 weeks were treated with the other drug (cross-over design) after a washout period. For evaluation of the therapeutic efficacy Hamilton Rating Scale for Depression, Comprehensive Psychopathological Rating Scale for Depression, Beck's Inventory and Global Rating Scales were used. All ratings indicated greater effectiveness for zimelidine as compared with desipramine, although the differences were not generally statistically significant. Only "somatic anxiety" on the Hamilton scale was significantly (P less than 0.05) in favour of zimelidine. Although both zimelidine and desipramine were well tolerated, the zimelidine patients reported significantly less severe anticholinergic adverse reactions. Of five patients who did not improve on zimelidine, three were then given desipramine but only one recovered completely. Of 10 patients who were switched over to zimelidine, 6 recovered completely and one moderately. Zimelidine produced strong inhibition of the uptake of 5-HT in platelets and a decrease in blood 5-HT after 2 weeks or longer treatment. The uptake of 5-HT in rat hypothalamic synaptosomes was reduced by about 50% and that of NA about 20% when incubated in the patients' plasma. All these effects seem to be mainly due to norzimelidine. Desipramine produced strong inhibition of the uptake of NA in hypothalamic synaptosomes but weak effect on the 5-HT uptake. Urinary MHPG tended to decrease during desipramine treatment but was not affected or tended to increase during zimelidine treatment.

Topics: Antidepressive Agents; Brompheniramine; Depressive Disorder; Desipramine; Female; Humans; Male; Norepinephrine; Psychiatric Status Rating Scales; Serotonin Antagonists; Zimeldine

In a randomized double-blind group comparison study of 40 patients with endogenous depression zimelidine appeared to be as effective an antidepressant as amitriptyline at 4 and 6 weeks using the Hamilton Rating Scale (HRS) and the Montgomery and Asberg Depression Rating Scale (MADRS). At 2 weeks there was a significantly better response (P less than 0.05) on zimelidine compared to amitriptyline on the clinician's global scale and 4 out of 10 items on the MADRS suggesting an early onset of action. A significant better response to zimelidine was seen on the item somatic anxiety (HRS) while the effect on sleep and appetite was better in the amitriptyline group. There were significantly more side effects, raw and corrected, in the amitriptyline-treated group. High steady state plasma concentrations of norzimelidine (greater than 800 nmol/l) which were significantly correlated with age (r = 0.8) were associated with a significantly poorer response suggesting that a lower dose than 200 mg in older patients may be appropriate.

Topics: Adult; Aged; Amitriptyline; Antidepressive Agents; Brompheniramine; Depressive Disorder; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

Depressive patients seen at hospital clinics are likely to be unrepresentative in terms of treatment response. In this study patients were always seen at their general practitioners' surgeries for assessment by specialists after selection as being in need of antidepressant treatment. The Research Diagnostic Criteria for major or minor depressive illness and a Hamilton Depression (Ham-D) score of at least 10 were required for inclusion, using the Present State Examination as a basis for interview. Patients were seen at weekly intervals, alternatively by practitioner and assessor for further Ham-D ratings, completion of the Kellner Sheffield Self-Rating test (KSSRT), event record and side effect checklist. Patients were randomly and blindly allocated to either zimelidine or amitriptyline dispensed identically at dosages of 100 mg and 75 mg at night, rising to 200 mg and 150 mg after two weeks. At four weeks there was no significant difference between the improvement found with zimelidine and amitriptyline or either the Ham-D or the KSSRT. Amitriptyline patients tended to gain and zimelidine patients to lose weight; difference significant. Other amitriptyline side effects were not found in those taking zimelidine, the latter tending to suffer diarrhoea. Preliminary analysis shows no relationship between clinical response and plasma level of either compound.

Topics: Adult; Amitriptyline; Antidepressive Agents; Brompheniramine; Depressive Disorder; Family Practice; Humans; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

Various studies have demonstrated that depressive symptoms are a frequent and important problem in general practice. Zimelidine has been shown to have effective antidepressant activity. A controlled double-blind trial was set up to compare the efficacy and side effects of zimelidine when given as a single daily dose (200 mg night or morning) and when given as a divided dose (100 mg b.d.). These three dosage schedules were studied. The trial was conducted among patients attending their general practitioners and suffering from a depressive disorder. Using one of the three dosage schedules, these patients were treated with zimelidine for a minimum period of 6 weeks. Symptom severity was measured by means of the Hamilton Rating Scale for Depression and the side effects assessed using an adverse event record and a symptom checklist. The findings are discussed.

Topics: Adult; Aged; Antidepressive Agents; Brompheniramine; Depressive Disorder; Family Practice; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Pyridines; Zimeldine

Topics: Animals; Anthracenes; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Maprotiline; Pyridines; Rats; Zimeldine

Topics: Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Desipramine; Double-Blind Method; Humans; Pyridines; Time Factors; Zimeldine

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (less than 20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (greater than 20 ng/ml). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a significant (P less than 0.05) positive correlation with age. The mean value of the uptake of 14C-5-HT in the patient's platelets, when measured before the treatment, was significantly (P less than 0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of 14C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of 14C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of 14C-5-HT in rat synaptosomes, but a marked inhibition of uptake of 14C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of 3H-NA in rat synaptosomes incubated in the patient's plasma was strongly inhibited by desipramine treatment but only slightly affected by zimelidine.

Topics: Animals; Antidepressive Agents; Blood Platelets; Brompheniramine; Depressive Disorder; Desipramine; Female; Humans; In Vitro Techniques; Male; Norepinephrine; Pyridines; Rats; Serotonin; Synaptosomes; Zimeldine

Adverse experiences during licensed treatment with the antidepressant serotonin (5-HT) reuptake inhibitor zimeldine in Sweden are presented. Data were obtained from a written inquiry of 694 patients and 67 reports to the Medical Products Agency. The spectrum of adverse symptoms was in agreement with those reported in previous studies on zimeldine. The most frequent adverse experiences were headache, nausea, myalgia, signs of liver function disturbance, arthralgia, neurological symptoms, fever and insomnia. No new case of the Guillain-Barré syndrome was found. The estimated frequency of the zimeldine-induced hypersensitivity syndrome (HSS), comprising fever, myalgia and/or arthralgia and signs of liver function disturbance, ranged from 1.4% to 13% in the inquiry and from 0.63% to 3.4% in the report part of the study. Adverse experiences usually had a considerably higher incidence during the first 6 weeks of zimeldine treatment than thereafter. This is in agreement with the clinical experience that most of the adverse reactions occur early during zimeldine treatment. However, a number of adverse experiences did occur with a later onset. This may justify a prolongation of the compulsory 4 weeks' testing of liver function that is required during licensed treatment. There were significantly fewer patients who developed fever among the patients who had experienced previous zimeldine treatment than among those who had not. Otherwise there was no statistically significant difference in frequency of adverse symptoms between these two groups. Consequently zimeldine treatment per se does not seem to predispose to development of an HSS or other types of adverse reactions during subsequent therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Depressive Disorder; Drug Approval; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neurologic Examination; Zimeldine

Five patients who reacted with the hypersensitive syndrome to zimeldine showed no reaction to one of two other selective 5-HT reuptake inhibitors, citalopram or paroxetine. This further strengthens the impression that the mechanism for the hypersensitivity syndrome induced by zimeldine does not seem to be related primarily to the 5-HT reuptake inhibition as such.

Topics: Aged; Aged, 80 and over; Antidepressive Agents; Citalopram; Combined Modality Therapy; Depressive Disorder; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Liver Function Tests; Male; Paroxetine; Piperidines; Serotonin Antagonists; Zimeldine

Topics: Depressive Disorder; Fluoxetine; Humans; Risk Factors; Serotonin Antagonists; Zimeldine

The results of pharmacokinetic studies of two recent 5-HT uptake inhibitors, zimelidine and fluoxetine, have pointed to the inadequacy of open-dose rising studies for establishing the most appropriate dose of new antidepressants. High plasma concentrations of the active metabolites, norzimelidine and norfluoxetine, were associated with a poorer therapeutic response in patients suffering from major depression. High drug plasma concentrations are also associated with increased side effects. Large fixed-dose placebo controlled studies with fluoxetine have confirmed the findings of the small pharmacokinetic study that lower doses are more effective. Fixed-dose pharmacokinetic studies are recommended as part of the program to establish the best dose of new antidepressants.

Topics: Depressive Disorder; Dose-Response Relationship, Drug; Fluoxetine; Humans; Zimeldine

Topics: Adult; Depressive Disorder; Drug Hypersensitivity; Female; Fluoxetine; Humans; Middle Aged; Zimeldine

The first of a series of 5HT reuptake inhibitors, zimelidine was withdrawn because of associated hypersensitivity reactions. There was concern that such reactions might be seen with other compounds of this class. Two depressed patients who had a sensitivity reaction to treatment with zimelidine were crossed over to treatment with fluoxetine and no abnormalities were observed. Both patients remained well during uneventful long term treatment with fluoxetine.

Topics: Chemical and Drug Induced Liver Injury; Depressive Disorder; Drug Hypersensitivity; Fluoxetine; Humans; Middle Aged; Polyradiculoneuropathy; Syndrome; Zimeldine

The original antidepressants, tricyclics and MAO inhibitors, increase the availability in the brain of both 5-HT and NA. Prompted by clinical findings suggestive of 5-HT disturbances in depression, drugs were developed that increase 5-HT selectively. Data are presented that suggest that broad-spectrum compounds may provide better conditions for antidepressant effects than the 5-HT-selective ones. The hypothesis is proposed that 5-HT potentiators are partial antidepressants, in that they predominantly reduce the anxiety/aggressive component of the depressive syndrome, and deserve to be tested in conditions with heightened anxiety and/or aggression irrespective of the nosological diagnosis. Tentative evidence relates diminished 5-HT metabolism to disordered impulse control. Based on these data, trials of 5-HT potentiators in impulse control disorders unrelated to aggressive drives seem warranted.

Topics: 5-Hydroxytryptophan; Aggression; Antidepressive Agents; Anxiety; Brain; Depressive Disorder; Desipramine; Humans; Hydroxyindoleacetic Acid; Norepinephrine; Serotonin; Zimeldine

Topics: Depressive Disorder; Double-Blind Method; Humans; Hydroxyindoleacetic Acid; Maprotiline; Methoxyhydroxyphenylglycol; Zimeldine

Topics: Amitriptyline; Antidepressive Agents; Depressive Disorder; Desipramine; Humans; Nortriptyline; Sleep; Sleep Stages; Zimeldine

Topics: Brain; Depressive Disorder; Fluoxetine; Humans; Propylamines; Receptors, Serotonin; Trazodone; Zimeldine

The sedative or excitatory effects of drugs are difficult to evaluate in patients with depression, where sleep disturbances and tiredness in the daytime belong to the clinical manifestations of the psychiatric disorder. A refined method of vigilance measurement, based on the EEG spectra, together with proper statistical analysis of the data, is helpful for correct interpretation of the data. In two groups of patients with depression, the intensity of sleep disturbances was considered as a background variable in partial correlations, reflecting the relationships between vigilance and drug concentration in a more specific way. It was shown that the sedative effect of maprotiline interferes with the increased vigilance in the patients, with improved night sleep after treatment. As a result, the patients do not experience decreased vigilance although maprotiline has a sedative action. The results obtained in the patients treated with beta-blockers suggest that the drug itself has no sedative effect but the patients suffer from decreased vigilance in the daytime, caused by the sleep disturbances and depression.

Topics: Anthracenes; Arousal; Attention; Depressive Disorder; Electroencephalography; Evoked Potentials; Humans; Maprotiline; Metoprolol; Zimeldine

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MHPG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.

Topics: Adult; Aged; Bipolar Disorder; Depressive Disorder; Desipramine; Female; Glycols; Humans; Kinetics; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Zimeldine

Topics: Depressive Disorder; Drug Interactions; Emotions; Female; Humans; Male; Methylphenidate; Zimeldine

Plasma levels of maprotiline, zimelidine, and their respective demethylated metabolites were analyzed, and their relationship to the clinical response was examined, in 60 depressed patients given the drug treatment for 4 weeks. Significant correlation was found between zimelidine and norzimelidine levels (r = 0.531; p less than 0.05) as well as between the steady-state levels of total zimelidine and concentration of the drug 12 h after a single dose (r = 0.753; p less than 0.001). The ratios of drugs and their metabolites in individual patients remained remarkably constant throughout the study. Significant correlations between Hamilton Depression Rating Scale (HAMD) scores and plasma levels of total maprotiline (r = 0.613; p less than 0.05) or norzimelidine (r = -0.552; p less than 0.05) were observed in subgroups of retarded depressives on day 14, and between HAMD scores and norzimelidine levels in retarded depressives (r = 0.703; p less than 0.02) and all patients (r = 0.436; p less than 0.02) on day 28. Both maprotiline and zimelidine produced marked decreases in mean HAMD scores by the end of treatment, but the overall clinical response between the various subgroups was not significantly different (x2 = 3.15; df = 3). Responders and nonresponders to treatment could not be distinguished by mean plasma levels of drugs or their metabolites when all patients were considered. However, a significant difference was found in maprotiline levels between responders and nonresponders within a subgroup of retarded depressives.

Topics: Anthracenes; Chromatography, Gas; Depressive Disorder; Humans; Maprotiline; Psychiatric Status Rating Scales; Zimeldine

Somatostatin is a hypothalamic tetradecapeptide with many central nervous system actions. We investigated a potential role for altered somatostatin activity in affective disorder by measuring somatostatin in the cerebrospinal fluid (CSF) of 47 patients with affective disorder and of 39 normal volunteers. Medication-free depressed patients showed significantly lower levels of CSF somatostatin than normal volunteers (p less than .001) or patients during the improved state (p less than .01). Somatostatin levels were significantly and inversely correlated with duration of sleep on the night of the lumbar puncture (p less than .05). Treatment with carbamazepine reduced CSF somatostatin (p less than .01) in contrast to the absence of effect of imipramine, desmethylimipramine, and lithium carbonate and the significant increase in CSF somatostatin seen in a small group of patients treated with zimelidine. The implications of these findings with respect to attempts to explore the neurobiology of depression are discussed.

Topics: Bipolar Disorder; Carbamazepine; Depressive Disorder; Desipramine; Humans; Imipramine; Lithium; Lithium Carbonate; Somatostatin; Zimeldine

Thirteen cases of the Guillain-Barré syndrome are reviewed, all occurring with a similar relationship to recent commencement of treatment with the antidepressive drug zimeldine. The risk of developing Guillain-Barré syndrome was increased about 25-fold among patients receiving zimeldine, as compared with the natural incidence of the disorder. The cases described provide strong evidence that Guillain-Barré syndrome may occur as a specific, probably immunologically mediated, complication of drug therapy.

Topics: Aged; Depressive Disorder; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Polyradiculoneuropathy; Risk; Zimeldine

Sixteen patients with a major depressive disorder underwent a Dexamethasone Suppression Test, and 15 of these patients were given intravenous methylphenidate and their mood response recorded. There was no association between the Dexamethasone Suppression Test and mood response to methylphenidate. Neither of these markers predicted clinical antidepressant response with zimelidine, although among zimelidine nonresponders, a clinical improvement upon the addition of lithium was predicted by a positive mood response to methylphenidate.

Topics: Adolescent; Adult; Affect; Depressive Disorder; Dexamethasone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Lithium; Lithium Carbonate; Male; Methylphenidate; Middle Aged; Prognosis; Psychiatric Status Rating Scales; Zimeldine

In this review, an attempt has been made to show how the tricyclic and non-tricyclic ("second generation") antidepressants, while differing widely in their acute pharmacological profiles, have a similar effect on central neurotransmission following their chronic administration. Animal models of depression and studies in depressed patients emphasize the importance of adrenergic receptor malfunction in the aetiology of the disease. Experimental and clinical studies suggest that all chronically administered antidepressants, irrespective of their acute pharmacological profile, can normalize central noradrenergic receptor function. Such a hypothesis helps to explain the slow duration in onset of the antidepressant effect and similar therapeutic efficacy of all forms of treatment.

Topics: Animals; Antidepressive Agents; Brain; Depressive Disorder; Disease Models, Animal; Dopamine; Humans; Mianserin; Neurotransmitter Agents; Nomifensine; Rats; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Reserpine; Synaptic Transmission; Trazodone; Zimeldine

The therapeutic efficacy, tolerability and pharmacokinetics of zimeldine in elderly depressed patients were evaluated after administration of different doses of the drug in once daily evening doses. The doses of zimeldine were 100 mg during the first 2 weeks, 150 mg during the next 2 weeks and 200 mg during the last 2 weeks. Nine of the 11 patients (mean age 78 years) included in the study completed the 6-week treatment period, and all nine improved according to the Hamilton depression rating scale. The drug was well tolerated and the side effects were few and mild. No influence of clinical importance was noted in haematology, liver and kidney functions, EEG, blood pressure or pulse rate. Steady-state plasma concentrations of zimeldine, and its active metabolite norzimeldine, were achieved in most cases after 1 week of treatment in each dose regimen. The plasma concentrations increased linearly with the increase in dose. The maximal interindividual variations in plasma concentrations were 8-fold for zimeldine and 3-fold for norzimeldine . The plasma levels of both zimeldine and norzimeldine were higher in the elderly than reported earlier in younger patients. The ratio of norzimeldine/zimeldine concentrations was reduced in the elderly, indicating a reduction of the metabolic capacity. The results suggest that zimeldine can be administered in a once daily dosage regimen to elderly patients, but they should be given a lower dose than younger patients.

Topics: Aged; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kinetics; Male; Zimeldine

Topics: Carbamazepine; Chronic Disease; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Lithium; Middle Aged; Phenelzine; Tranylcypromine; Tryptophan; Zimeldine

Topics: Amitriptyline; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Humans; Statistics as Topic; Zimeldine

Effects of electroconvulsive treatment (ECT) and lithium carbonate on norepinephrine metabolism were investigated in eight patients with primary, major depressions. A series of 12 ECTs reduced urinary norepinephrine and normetanephrine output significantly, and showed a tendency to reduce urinary vanillylmandelic acid output as well as whole-body norepinephrine turnover. Treatment with lithium carbonate significantly reduced urinary norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid output as well as whole-body norepinephrine turnover. These findings point to a common effect of antidepressant treatments since they are similar to results produced by administration of three other types of antidepressant drugs: clorgiline, a specific monoamine oxidase A inhibitor; desipramine, a relatively specific norepinephrine reuptake Inhibitor; and zimelidine, a relatively specific serotonin reuptake Inhibitor. These drugs reduce total production of norepinephrine and/or its major metabolites in depressed patients. Thus, five antidepressant treatments with different mechanisms of action have a common overall effect on the system.

Topics: Brompheniramine; Clorgyline; Depressive Disorder; Desipramine; Electroconvulsive Therapy; Female; Humans; Lithium; Lithium Carbonate; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Normetanephrine; Vanilmandelic Acid; Zimeldine

Two hundred inpatients suffering from primary depressive illness were studied. Seventy eight of the patients were treated by electroconvulsive therapy (ECT) and 122 patients received antidepressant medication. Response to ECT and antidepressant medication at 4 weeks showed a curvilinear relationship to Newcastle scores. Patients with Newcastle scores in the middle range (4-8) showed significantly higher percentage improvement than those with low (0-3) and high (9-12) scores. Ninety five patients with unipolar depression who received lithium therapy for one year were also studied. Response to lithium showed a linear relationship to Newcastle scores in these patients. It is suggested that these differences in response to antidepressant therapies reflect the heterogeneity of depressive illness.

Topics: Amitriptyline; Clomipramine; Combined Modality Therapy; Depressive Disorder; Electroconvulsive Therapy; Female; Humans; Lithium; Lithium Carbonate; Male; Middle Aged; Zimeldine

Topics: Depressive Disorder; Humans; Zimeldine

The aim of this study was to evaluate the safety of zimeldine, a 5-HT reuptake inhibitor, in the long-term treatment of depressive disorders. The study was an open label, multicentre investigation involving 147 patients who were suffering from depressive illness and who needed long-term anti-depressant treatment. Sixty-five patients completed the intended treatment period of 1 year, 75 terminated prematurely, and 7 are still in the programme. The reasons for termination were mainly ineffectiveness of the drug and adverse reactions. During the long-term treatment the most common emergent symptoms were, in order of decreasing frequency, dizziness, dry mouth, sleep disorders, sweating, tremor, nausea and headache. The side-effects were, however, mild and they generally decreased during the treatment period. No new adverse symptoms were reported. In the long-term treatment group, body weight showed a slight mean decrease. Clinical chemistry and cardiovascular investigations were judged to show no changes of clinical importance. It is concluded that zimeldine was shown to be a safe drug in this 1-year treatment programme of depression.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Body Weight; Child; Creatinine; Depressive Disorder; Electrocardiography; Female; Humans; Male; Middle Aged; Nausea; Sleep Wake Disorders; Time Factors; Zimeldine

Changes in diagnostic criteria have shown a trend towards a broader definition of depression. Thus, a number of patients who would previously have been considered to be suffering from anxiety states are now classified as having major depressive illness according to the criteria of the Diagnostic Statistical Manual III. Despite this, such patients show a good response to antidepressant drugs (compared to placebo) if their severity of depression is above 15 on the Hamilton depression scale. It therefore seems likely that there is a common biological substrate underlying both anxiety states and depressive illness, but this issue remains somewhat controversial. The suggestion that the 5-HT system is involved in the mediation of anxiety is considered. Further evidence is required before definite conclusions can be drawn, but it seems clear that anxiolytic activity is not dependent on sedative properties.

Topics: Amitriptyline; Anxiety Disorders; Depressive Disorder; Humans; Serotonin; Sleep Initiation and Maintenance Disorders; Zimeldine

Epidemiological data indicate that the incidence of classical melancholia is lower among the elderly; however, light, atypical or secondary depressions appear to become more common during old age. Biochemical changes that occur with age or in association with dementia, may increase vulnerability to affective disorders. Preliminary studies show that zimeldine is an effective antidepressant with low cardiotoxicity and few anticholinergic side-effects, and it appears that the drug is well tolerated by the elderly. Drug regimens need to be carefully tailored to the elderly patient's requirements, however, as first-pass metabolism is reduced in some patients. An objective test to differentiate dementia from depression would be extremely valuable. Unfortunately, no such test has yet been found. The dexamethasone suppression test, for example, has proved to be unreliable in this context.

Topics: Aged; Aging; Brain Chemistry; Dementia; Depressive Disorder; Humans; Zimeldine

In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.

Topics: Adult; Aged; Animals; Antidepressive Agents; Blood Platelets; Brompheniramine; Depressive Disorder; Desipramine; Double-Blind Method; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Hypothalamus; Male; Methoxyhydroxyphenylglycol; Middle Aged; Norepinephrine; Pyridines; Rats; Serotonin; Synaptosomes; Zimeldine

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aged; Animals; Antidepressive Agents; Brain; Brompheniramine; Dementia; Depressive Disorder; Humans; Male; Rats; Receptors, Dopamine; Receptors, Serotonin; Research; Serotonin; Sexual Behavior, Animal; Structure-Activity Relationship; Tetrahydronaphthalenes; Zimeldine

The major sleep characteristics of depression are summarized and new EEG sleep studies of antidepressants, including preliminary data on desipramine and zimelidine, are described. The relationship of steady-state plasma amitriptyline levels to REM sleep and the use of EEG sleep measures as predictors of clinical response to tricyclics will also be discussed. The effects of antidepressant agents on sleep are immediate and pronounced, and studies of these drug-induced effects may also represent a rational method for drug classification.

Topics: Amitriptyline; Antidepressive Agents; Brompheniramine; Depressive Disorder; Desipramine; Electroencephalography; Humans; Sleep; Sleep, REM; Zimeldine

In a previous double-blind, 3-week study we compared the effect of clomipramine + placebo with clomipramine + tryptophan in 24 patients with endogenous depression. The patients in the latter group showed a significantly more rapid improvement than those in the former group, especially with regard to the depression-anxiety cluster of symptoms. These results prompted us to perform a similar study in which zimelidine, a more specific inhibitor of 5-HT reuptake, was used instead of clomipramine. In other respects the design was practically identical to that used in the previous study. Unexpectedly, tryptophan in combination with zimelidine, was not superior to placebo + zimelidine with respect to antidepressant activity. In comparison with the previous study, the antidepressant action of zimelidine showed no statistically significant difference from clomipramine. However, the patients tended to show a more prompt response after zimelidine + placebo than after clomipramine + placebo. The changes in CSF metabolites were likewise different in the two studies. In the two studies taken together 12 out of 49 patients showed prompt improvement within one week. This raises the question whether the therapeutic response to antidepressant drugs necessarily involves a delay as is generally assumed. Side effects were remarkably few and mild in the second study.

Topics: Biogenic Amines; Brompheniramine; Clomipramine; Depressive Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Psychiatric Status Rating Scales; Serotonin Antagonists; Tryptophan; Zimeldine

Topics: Adult; Amitriptyline; Antidepressive Agents; Blood Pressure; Brompheniramine; Cardiovascular Diseases; Depressive Disorder; Dibenzazepines; Female; Heart Rate; Humans; Male; Mianserin; Myocardial Contraction; Pyridines; Zimeldine