Comparison between zimelidine and desipramine in endogenous depression. A cross-over study

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.     

Weight change in older depressed patients during acute pharmacotherapy with paroxetine and nortriptyline: a double-blind randomized trial.

The authors examined weight change in 32 elderly patients treated for 12 weeks with either nortriptyline or paroxetine during acute-phase pharmacotherapy. Random assignment to treatment and double-blind assessment of weight change were performed, including ascertainment of premorbid (i.e., pre-depression) weight. Pretreatment severity of depression was correlated with weight loss during the depressive episode and depression-related weight loss, in turn, correlated with weight regained during antidepressant treatment. There was no differential weight change associated with nortriptyline vs. paroxetine. Rather, subjects in both groups approximated their premorbid weights by 12 weeks of acute-phase pharmacotherapy with either agent. However, additional investigation of weight change during continuation and maintenance pharmacotherapy is necessary and would be clinically useful for the long-term management of elderly patients with depression.     

Depression,antidepressants, and plasma DBH

Plasma levels of dopamine-β-hydroxylase (DBH) were determined in 16 unmedicated patients with major depressive episodes (nonpsychotic) and in an equal number of normal subjects, before and after 4 weeks of treatment with tricyclic antidepressants. Some eight patients were treated with amitriptyline, and the remainder received desipramine. The controls remained medication free during the entire experimental period. Degrees of depression were quantified before and after treatment with the Hamilton Rating Scale of Depression (HRSD). There were no significant differences between the depressed patients and the controls on levels of DBH. Similarly, there were no within-group, pre-posttreatment differences on the enzyme levels in either group. Pre-and posttreatment HRSD scores did not correlate with corresponding plasma DBH levels. Plasma levels of amitriptyline, nortriptyline (product of amitriptyline in the body), and desipramine at the end of 4 weeks of treatment also failed to correlate with the enzyme levels.     

Simultaneous measurement of various antidepressants in the plasma of depressed patients by high performance liquid chromatography

A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nortriptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.     

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. I. Clinical findings

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.     

Excess fatality from desipramine in children and adolescents

OBJECTIVE: To compare the case fatality rate (CFR) from desipramine ingestion in children and adolescents with that of other tricyclic antidepressants. METHOD: All mentions of desipramine, amitriptyline, imipramine, nortriptyline, and doxepin in children and adolescents recorded in the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 to 2002 were analyzed. The CFR for each drug was defined as the ratio of the number of deaths/number of mentioned exposures. RESULTS: There were 24 fatalities in children younger than 6 years old (desipramine, n=10; amitriptyline, n=7; doxepin, n=3; imipramine, n=3; nortriptyline, n=1) and 144 fatalities in older children and adolescents (desipramine, n=56; amitriptyline, n=30; doxepin, n=16; imipramine, n=31; nortriptyline, n=11). The CFR from desipramine was significantly higher compared with the other tricyclic antidepressants in children younger than 6 years old (chi=36, p<.001) and in older children and adolescents (chi=155, p<.001). The CFR from desipramine exceeded that of amitriptyline, doxepin, imipramine, and nortriptyline by 7- to 8-, 4-, 6- to 12-, and 7- to 10-fold, respectively. CONCLUSIONS: The excess CFR from desipramine in children and adolescents and the reports of sudden death in children treated with therapeutic doses call for caution in prescribing desipramine to children and adolescents.     

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings

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.     

A double-blind comparative trial of zimelidine, amitriptyline, and placebo in patients with mixed anxiety and depression

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.     

Reduced REM latency predicts response to tricyclic medication in depressed outpatients

Forty-two outpatients with major depressive disorder entered a double-blind, randomized trial of either desipramine or amitriptyline for a minimum of 6 weeks. Pretreatment polysomnographic and clinical measures were used to predict response. Response was defined as a 17-item Hamilton Rating Scale for Depression score less than or equal to 9 at the end of treatment. There was a 61.1% response rate for patients treated with amitriptyline and a 66.7% response rate for patients treated with desipramine. Reduced REM latency (2-night mean less than or equal to 65.0 min) predicted a positive response to these tricyclic antidepressants. REM latency did not differentiate between desipramine or amitriptyline responders. More patients with reduced REM latency (80%) responded to treatment compared with patients with nonreduced REM latency (50%). The 80% response rate in reduced REM latency depressed patients confirms our previous findings in a mixed inpatient and outpatient sample. Contrary to our hypothesis, in this sample, endogenous depression was not associated with a good response to tricyclic medication.     

The effect of desipramine on body weight in depression

Twenty-six patients with major depressive disorder were treated with desipramine for 4 weeks to determine the effect of the drug on body weight. Responders to desipramine showed a weight gain only at Weeks 3 and 4; nonresponders had a nonsignificant loss of weight. The increase in body weight of the responders was independent of dosage, sex, and hospitalization status. These findings suggest that the small increase in body weight that occurs in patients taking desipramine is associated with treatment response. In addition, desipramine may be a valuable treatment alternative for those patients in whom excessive weight gain is undesirable.     

Plasma and erythrocyte levels of tricyclic antidepressants in depressed patients.

Plasma and red blood cells (RBCs), amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyl doxepin levels were measured in depressed inpatients during steady-state kinetics. A strong positive correlation between the drug levels in plasma and RBCs was found for amitriptyline, nortriptyline, desipramine, and desmethyl doxepin. However, at a given plasma level, up to a 6-fold interindividual variation in the RBC drug levels was found. The correlations between plasma and RBC imipramine and doxepin levels were low. The interindividual variation in the RBC-plasma tricyclic level ratios was large enough to warrant further clinical studies on the relationship between efficacy and pharmacokinetics of tricyclic antidepressants.     

A double-blind evaluation of zimelidine in comparison to placebo and amitriptyline in patients with major depressive disorder

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.     

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients

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.     

Antidepressant prescribing in nursing homes: is there a place for tricyclics?

OBJECTIVE: To deduce a model describing physicians' choice of antidepressants for treating elderly nursing home patients. METHODS: Subjects were geriatric residents of 137 skilled nursing facilities who regularly received an antidepressant medication for at least one month (n = 3,440, 28% of all residents). Reasons for prescribing antidepressants and physicians' diagnoses of depression and dementia were identified by medical record audit. Residents were grouped by dementia and antidepressant target symptoms (depression, or one or more non-psychiatric symptoms, i.e. insomnia, pain, incontinence, itching). RESULTS: Selective serotonin reuptake inhibitors (SSRIs) were prescribed preferentially over tricyclic antidepressants (TCAs) for treating depression in both demented and non-demented residents, but TCAs were nine times more likely to be prescribed for treating non-psychiatric target symptoms alone. When non-psychiatric target symptoms were present without depression or dementia, both amitriptyline and nortriptyline prescribing was increased, but amitriptyline appeared to be the antidepressant of choice. In all subgroups examined, its use was two to five times more prevalent when such symptoms were present. In patients with dementia, amitriptyline prescribing declined whether or not non-psychiatric target symptoms were present, but nortriptyline prescribing did not; nortriptyline was three times more likely than amitriptyline to be prescribed in the presence of dementia. CONCLUSIONS: Physicians prescribe anticholinergic TCAs principally to treat common non-depressive symptoms in nursing home residents, preferring SSRIs for uncomplicated depression and depression with dementia. They tend to avoid prescribing anticholinergic TCAs other than nortriptyline when they recognize a patient as demented. The data suggest that physicians employ a decision model for antidepressant prescribing that simultaneously recognizes the utility of TCAs in treating non-psychiatric symptoms and the anticholinergic vulnerability of older, especially demented, patients. Whether or not this model leads to optimal patient management requires further study.     

Neuroendocrine dysfunction and response to tricyclic antidepressants

Patients with DSM-III unipolar major depression (N = 26) were treated with tricyclic antidepressants after 2 weeks of inpatient drug-free observation and neuroendocrine testing. Medication was prescribed with individualized dosages and was monitored with blood levels. Treatment response (greater than or equal to 50% decrease in Hamilton depression score after 4 weeks) was seen in 6 of 13 patients given desipramine and 7 of 13 given nortriptyline. Of the 13 nonresponders, 9 accepted treatment with another drug and/or ECT; 5 responded. Thus, 18 of the 26 patients responded to treatment. Abnormal pretreatment DST was correlated with increased responsiveness to treatment, although all patients had a high probability of response.     

Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study

OBJECTIVE: This study compared nortriptyline and fluoxetine with placebo in the treatment of depression and in recovery from physical and cognitive impairments after stroke. METHOD: A total of 104 patients with acute stroke enrolled between 1991 and 1997 entered a double-blind randomized study comparing nortriptyline, fluoxetine, and placebo over 12 weeks of treatment. The majority of patients were recruited from a rehabilitation hospital in Des Moines, Iowa, but other enrollment sites were also used. Both depressed and nondepressed patients were enrolled to determine whether improved recovery could be mediated by mechanisms unrelated to depression. Nortriptyline in doses of 25 mg/day gradually increased to 100 mg/day or fluoxetine in doses of 10 mg/day gradually increased to 40 mg/day or identical placebo were given over 12 weeks. Response to treatment of depression for individual patients was defined as a greater-than-50% reduction in scores on the Hamilton Rating Scale for Depression and no longer fulfilling diagnostic criteria for major or minor depression. Improved recovery for a treatment group was defined as a significantly higher mean score from baseline to end of the treatment trial, compared with patients treated with placebo, on measures of impairment in activities of daily living and levels of cognitive and social functioning. RESULTS: Nortriptyline produced a significantly higher response rate than fluoxetine or placebo in treating poststroke depression, in improving anxiety symptoms, and in improving recovery of activities of daily living as measured by the Functional Independence Measure. There was no effect of nortriptyline or fluoxetine on recovery of cognitive or social functioning among depressed or nondepressed patients. Fluoxetine in increasing doses of 10-40 mg/day led to an average weight loss of 15. 1 pounds (8% of initial body weight) over 12 weeks of treatment that was not seen with nortriptyline or placebo. CONCLUSIONS: Given the doses of medication used in this study, nortriptyline was superior to fluoxetine in the treatment of poststroke depression. Demonstrating a benefit of antidepressant treatment in recovery from stroke may require the identification of specific subgroups of patients, alternative measurement scales, or the optimal time of treatment.     

Weight changes in postpartum women with remitted depression

OBJECTIVE: To compare weight loss after birth in women who took the antidepressants nortriptyline or sertraline or placebo in 2 clinical studies designed to prevent recurrent postpartum major depression. METHOD: Data were collected from 1995 to 2001. All subjects had at least 1 prior episode of Research Diagnostic Criteria- or DSM-IV-defined major depressive disorder. Data on weight were available for 467 weeks from 60 women who were weighed 8 times from 2 to 17 weeks postpartum. The dependent measures were weight at weeks 11 and 17 and weight change from weeks 2 to 17 postpartum. RESULTS: At week 17, the women's weights ranged from 109 to 268 lb. Their weight change ranged from +14 to -19 lb over the 15-week postpartum period (mean = -1.8, SD = 5.1 lb). After controlling for week 2 weights, the mean weights at week 17 for the women treated with nortriptyline, sertraline, or placebo were not significantly different. Of 60 women with 3 or more weight assessments, those who were randomly assigned to nortriptyline lost weight more rapidly than the other 2 groups; however, the mean weight change across all groups was only -1.8 lb (SD = 5.1 lb). CONCLUSIONS: Weight loss was not compromised by antidepressant pharmacotherapy. Postpartum weight retention occurred in this group of nondepressed women with previous histories of major depression independent of drug treatment.     

The prophylactic efficacy of tricyclic antidepressants--a five year followup

1. In order to evaluate the efficacy of antidepressants in the prevention of recurrent depression, a longitudinal life-table analysis was carried out involving 217 unipolar patients whose depressive symptoms had remitted following treatment with one of five standard tricyclics (imipramine, amitriptyline, desipramine, nortriptyline, and doxepin). 2. Following six months continued euthymic mood these patients were maintained on the medication to which they initially responded to in a clinical setting over a 5 year period. These patients were compared against a group of 28 individuals who were treated acutely for their depression and responded to one of the above the 5 standard antidepressants, but following 5-6 months continuation treatment were taken off the antidepressant at their own request. 3. Though there was a lower rate of relapse in patients receiving active medication vs the no treatment group, the frequency of relapse was high for the group on active drug. 4. Using the longitudinal life-table method of Fleiss there was a pessimistic-optimistic average relapse rate of 30%, 50%, and 60%, at 1, 2, and 3 years respectively while on active drug vs a 51%, 74%, and 83% relapse rate on no treatment. Overall 87 of 217 patients on active drug (40.1%) were observed to have suffered a depressive relapse over the 5 year course.     

A double-blind, placebo-controlled assessment of nortriptyline's side-effects during 3-year maintenance treatment in elderly patients with recurrent major depression

The authors assessed the severity of nortriptyline's side-effects in older patients with recurrent major depression during placebo-controlled, double-blind maintenance therapy. Data were from 37 patients completing 2-3 years of maintenance therapy; 29 were on nortriptyline and eight were on placebo. The authors detected a time-by-treatment interaction for dry mouth (greater in nortriptyline-treated patients), but no increased association of nortriptyline with constipation, weight change or orthostatic symptoms. Heart rate was consistently higher in nortriptyline-maintained patients as compared with placebo. The total 'side-effect' score on the Asberg Rating Scale, as well as complaints of physical tiredness, daytime sleepiness and nocturnal sleep disturbance, were related primarily to residual depression rather than treatment with nortriptyline.     

Somatic symptoms in depression and antidepressants

Somatic side effects of antidepressant medications and of depression and anxiety were quantified in depressed patients before and after 4 weeks of treatment with amitriptyline (N = 11), or desipramine (N = 12). The entire group showed significant posttreatment decreases in depression. Side-effect symptoms were significantly reduced after treatment in the amitriptyline group; less reduction was seen in the desipramine group. Significant correlations were demonstrated between levels of anxiety and side effect symptoms both before and after treatment. The reduction in side effect symptoms in the amitriptyline group can be explained by the drug's anxiolytic property. Our findings suggest that symptoms resembling antidepressant side effects seen in medicated depressed patients are influenced by the patient's clinical condition more than by the anticholinergic activity of moderate dosages of the antidepressant.