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PubMedDate not supplied

Percutaneous absorption of tricyclic antidepressants: amitriptyline, nortriptyline, imipramine, and desipramine.

The percutaneous absorption of amitriptyline, nortriptyline, imipramine, and desipramine as their hydrochloride salts in vivo was demonstrated without use of a vehicle using the hairless (hr-1/hr-1) mouse as an experimental model for human skin. After topical application of 2 mg of each compound in distilled water, followed by rapid evaporation of the water, concentrations were measured in heart, lung, brain, liver, and blood in 1-, 2-, 4-, and 6-hour study groups. Lung consistently demonstrated the highest concentrations for all four compounds while heart and liver had the lowest. Concentrations in heart remained essentially constant for all compounds during the 6-hour study period. The concentrations in solid tissues were much lower than those commonly seen in man after overdose, whereas the concentrations in blood resembled low therapeutic to toxic concentrations in humans. Percutaneous absorption may provide a feasible route of administration for the tricyclic antidepressants which may lead to improved compliance with fewer gastrointestinal side effects.

Amitriptyline↗
PubMed1985

Paradoxical sleep deprivation and the immobility response in the rat: effects of desipramine and phentolamine.

A series of experiments was conducted on the presumption that instrumental deprivation of paradoxical sleep (PS) has an effect comparable with that of antidepressant drug treatment in a behavioral paradigm, Porsolt's forced swim test. After long-term PS deprivation, we studied the duration of immobility, which can be markedly reduced by antidepressant drugs, using both the platform and the pendulum technique. In addition to a small common effect for PS deprivation, differences confirming the platform-pendulum controversy were also detected. Nonspecific platform effects are considered to explain these differences. In a second experiment it was shown that the small PS deprivation effect can be enlarged by desipramine treatment, suggesting similarities in the underlying mechanisms. In the third experiment, just before the end of the deprivation, phentolamine, a drug that blocks the rebound of PS, was administered. It reduced the effect of pendulum PS deprivation, suggesting that PS propensity is an important factor in the reduction of duration of immobility.

Animals↗
PubMed1989

A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy.

The tricyclic antidepressant drug desipramine (DMI) was evaluated in the treatment of young patients with attention deficit disorder with hyperactivity (ADDH) in an unselected sample of 62 clinically referred patients, 43 (69%) of whom previously responded poorly to psychostimulant treatment. The 42 children and 20 adolescents were assigned randomly to receive DMI (N = 31) or placebo (N = 31) for up to 6 weeks in a parallel groups, double-blind study. Clinically and statistically significant differences in behavioral improvement were found for DMI over placebo, at an average (+/- SEM) maximal daily dose of 4.6 +/- 0.2 mg/kg; 68% of DMI-treated patients were considered very much or much improved, compared with only 10% of placebo patients (p less than 0.001). DMI was well tolerated, even at the relatively high doses used. These findings suggest that DMI can be an effective treatment in the management of pediatric patients with ADDH, including patients who failed to respond to stimulants.

Adolescent↗
PubMed1989

A double-blind placebo controlled study of desipramine in the treatment ADD: II. Serum drug levels and cardiovascular findings.

In a 6-week study of children and adolescents with attention deficit disorder with hyperactivity (ADDH) in which desipramine (DMI) was highly effective and well tolerated, the mean maximal daily oral dose in the DMI-treated patients (N = 31) was 4.6 +/- 0.2 mg/kg. Additional data were obtained for 27 placebo nonresponders given DMI openly for 6 additional weeks following a nearly identical protocol and mean daily doses (total N = 58). Individual serum drug concentration varied widely at a given dose. The overall median serum DMI level was 152 ng/ml and in 6 of 56 cases with assayed serum (DMI), the level exceeded 500 ng/ml. Serum tended to be higher with older age and greater clinical improvement. Only small, clinically unimportant but statistically significant increases in diastolic blood pressure, heart rate, and electrocardiographic conduction parameters occurred. DMI-treated patients showed higher incidence during DMI treatment of sinus tachycardia and ECG evidence of intraventricular conduction defect (IVCD) of the right bundle branch block type, with two of these patients developing complete IVCD. Increases in ventricular rate and in ECG conduction parameters, as well as the incidence of IVCD, were higher in patients attaining serum levels of DMI above the median. These findings suggest that, although treatment with DMI at daily doses above 3.5 mg/kg may be needed in some cases of childhood ADDH, such doses require caution and monitoring of serum drug levels and ECG when they are used in the pediatric population.

Adolescent↗
PubMed1992

Growth deficits in children treated with desipramine: a controlled study.

Using multiple assessment methods, growth deficits in weight and height were examined in a clinical sample of children and adolescents with attention deficit hyperactivity disorder treated chronically (mean 14 months) with desipramine (DMI) and two comparison samples of children treated chronically with methylphenidate (MPH) and a not-treated group. Although there were statistically significant weight deficits in children treated with both DMI and MPH compared with normal controls, only those treated with MPH sustained height deficits that attained statistical significance. It appears that DMI may be an appropriate alternative for patients with stimulant-associated severe suppression of growth in height.

Adolescent↗
PubMed1992

Desipramine facilitation of cocaine abstinence in an adolescent.

An adolescent who was simultaneously dependent on cocaine and treated for attention-deficit hyperactivity disorder (ADHD) with dexedrine developed symptoms of severe depression followed by suicidal behavior. The patient was treated for cocaine craving, depression, and ADHD with desipramine on an inpatient adolescent unit for substance abusers with comorbid psychiatric disorder. The Minnesota Cocaine Craving Scale was used to monitor the cocaine craving. Issues about the strategies for the treatment of cocaine craving and the stimulant treatment/abuse dilemma are discussed with a special emphasis on comorbidity in adolescent substance abusers. Suicidal behavior related to cocaine abuse and craving and the application of the cocaine abstinence three phase model to an inpatient setting are illuminated.

Adolescent↗
PubMed1993

A double-blind placebo controlled study of desipramine in the treatment of ADD: III. Lack of impact of comorbidity and family history factors on clinical response.

A 6-week randomized, double-blind, placebo controlled trial of desipramine (DMI) in daily doses averaging 4 to 5 mg/kg for the treatment of children and adolescents with attention deficit disorder with hyperactivity (ADDH) was further analyzed. Investigators examined whether comorbidity of ADDH with conduct disorder, major depression, an anxiety disorder, or a family history of ADDH predicted response to DMI treatment. There was a highly significant effect of treatment with DMI in outcome assessments, but responses to DMI were indistinguishable in ADDH patients with and without a comorbid disorder or familial ADDH. Cases of "pure" ADDH (lacking comorbidity with depression, anxiety, or conduct disorder and having a positive family history of ADDH) showed a trend toward lesser placebo responses and a corresponding greater DMI-placebo difference. These findings suggest that (1) DMI is effective in simple, noncomorbid cases, (2) DMI is not selective for comorbid cases, but (3) a response to DMI can be obtained even in complex cases of ADDH with associated comorbidity.

Adolescent↗
PubMed1993

Methylphenidate and desipramine in hospitalized children: I. Separate and combined effects on cognitive function.

OBJECTIVE: The separate and combined effects of methylphenidate and desipramine on cognitive function were investigated in 16 psychiatrically hospitalized children with primary, secondary, and mixed features of attention-deficit hyperactivity disorder and mood disorder. METHOD: A double-blind, placebo controlled, crossover design was used to investigate drug effects on vigilance, short-term memory, visual problem solving, and higher-order learning. RESULTS: Methylphenidate alone improved vigilance, both drugs positively affected short-term memory and visual problem solving, and combined drugs affected learning of higher-order relationships. CONCLUSIONS: Separate and combined drug effects are related to the specific cognitive domain assessed and have implications for neurotransmitter models of action.

Arousal↗
PubMed1993

Desipramine treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette's syndrome.

OBJECTIVE: As many as 50% of patients with Tourette's syndrome (TS) also meet diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Since antipsychotics are of limited value in controlling the symptoms of ADHD and stimulants can exacerbate tics, alternative treatments are directly needed. The purpose of this study was the examination of the efficacy of desipramine (DMI) in the treatment of pediatric patients with chronic tic disorder (CTD; TS or chronic motor tics) + attention-deficit hyperactivity disorder (ADHD). METHOD: All pediatric patients with the diagnosis of CTD that were treated with DMI were ascertained from retrospective systematic chart reviews of a psychopharmacology clinic and a neurology service specialized in movement disorders. RESULTS: Of the 33 identified patients, 30 had comorbid CTD + ADHD and three had CTD alone. In all, 82% had significant improvement in CTD symptomatology and 80% significantly improved ADHD symptoms without major adverse effects over an average follow-up period of 16 months. CONCLUSIONS: Although the conclusions from this retrospective report can be seen as preliminary only until replicated in a controlled investigation, the magnitude and persistence of the response is encouraging and suggest a therapeutic role for DMI in the treatment of CTD + ADHD patients.

Adolescent↗
PubMed1993

A naturalistic study of 24-hour electrocardiographic recordings and echocardiographic findings in children and adolescents treated with desipramine.

OBJECTIVE: Recent studies assessing cardiovascular effects of desipramine (DMI) in pediatric patients consistently have found small, clinically benign, but statistically significant, increases in heart rate and electrocardiographic (ECG) conduction parameters. However, single, routine ECG recordings cannot fully assess potential infrequent rhythm disturbances. METHOD: We analyzed data from 24-hour ECG monitoring, two-dimensional Doppler echocardiography, and expert clinical cardiac examination of DMI-treated patients. Subjects were 71 children (N = 35) and adolescents (N = 36) receiving long-term treatment (means +/- SD = 1.5 +/- 1.2 years, median = 1.0 year) with DMI (means +/- SD = 3.5 +/- 1.6 mg/kg). RESULTS: Compared with previous observations in untreated healthy children. DMI-treated patients had significantly lower rates of sinus pauses and junctional rhythm, but significantly higher rates of single or paired premature atrial contractions and runs of supraventricular tachycardia. There was an association between DMI serum levels and paired premature atrial contractions, but no other associations were detected. CONCLUSIONS: These findings support the impression from previous ECG studies that DMI-associated cardiac effects in pediatric patients are quite benign. Nevertheless, it remains to be ascertained whether even minor cardiac abnormalities may predict later, evidently rare, adverse cardiovascular effects that may include sudden death.

Adolescent↗
PubMed1994

Effects of desipramine on autonomic control of the heart.

OBJECTIVE: To assess the effects of desipramine (DMI) on autonomic control of the heart. METHODS: Blood pressure, RR interval (the time between successive heart beats), and RR interval variability, a noninvasive measure of autonomic control of the heart, were assessed in 13 subjects younger than 30 years old. RESULTS: DMI treatment was associated with an increase in blood pressure, a decrease in RR interval, and a decline in low and high frequency RR interval variability. CONCLUSIONS: These preliminary data suggest that, in young people, DMI treatment produces a substantial decrease in parasympathetic input to the heart and an increase in the ratio of sympathetic to parasympathetic input, changes that in certain circumstances have been associated with an increased risk of arrhythmia. In exploring the cardiac effects of the tricyclic antidepressants (TCAs) in young people, the impact of TCAs on autonomic input to the heart should be examined.

Adolescent↗
PubMed1994

Response to desipramine treatment in adolescent depression: a fixed-dose, placebo-controlled trial.

OBJECTIVE: To determine the efficacy and tolerability of the tricyclic antidepressant desipramine (DMI) in the treatment of DSM-III-R-diagnosed major depressive disorder in adolescents. METHOD: Sixty adolescents (42 female, 18 male; aged 15 to 19 years) diagnosed with major depressive disorder using clinical interview and Schedule for Affective Disorders and Schizophrenia for School-Age Children were randomized to receive either DMI (200 mg daily in divided doses) or placebo for six consecutive weeks following a 1-week placebo period. Treatment outcome was determined using the Hamilton Depression Rating Scale and the Beck Depression Inventory. Tolerability was determined using a symptom side effects scale. In addition, a variety of laboratory and cardiovascular monitoring was performed. RESULTS: No significant differences in treatment outcome between DMI- and placebo-treated groups were determined. Neither DMI, nor its metabolite 2-hydroxy-DMI, nor their ratio, was positively correlated to treatment outcome. The DMI group endorsed more side effects but there were no significant between-group differences in any laboratory, electrocardiographic, or other cardiovascular parameters apart from heart rate, which was increased in the DMI-treated group (p = .03). CONCLUSIONS: Given the findings of this study and our review of previously published reports of tricyclic antidepressant treatment in this population, the routine use of short-term (6 weeks) DMI in the treatment of adolescent depression is not supported by the data on hand. Further investigations into what constitutes optimal psychopharmacological treatment of adolescent depression are warranted.

Adolescent↗
PubMed1995

Electrocardiographic changes during desipramine and clomipramine treatment in children and adolescents.

OBJECTIVE: With the increased use of tricyclic antidepressants in children, and several reports of several sudden deaths associated with desipramine (DMI) treatment, systematic study of their cardiac effects is indicated. In the present study, DMI's and clomipramine's (CMI) short-term effects on the electrocardiogram (ECG) were compared, as well as the long-term effects of CMI. METHOD: The ECGs of 47 children and adolescents in treatment trials were examined at baseline, after 5 weeks of CMI and of DMI treatment, and during CMI maintenance (mean duration 24.6 months). RESULTS: At 5 weeks of CMI and of DMI treatment, the heart rate, PR, QRS, and QT-corrected (QTc) intervals on ECG were significantly increased from baseline (p < .05); DMI increased PR and QRS intervals more than CMI (p < .05), and CMI increased QTc more (p < .05). Tachycardia was the most common change (36%). More patients experienced an incomplete intraventricular conduction delay during DMI treatment (23%, 9/39) than during CMI (2%, 1/47) (p < .05). Four patients (9%) acutely developed a prolonged QTc during either DMI or CMI. Long-term maintenance ECGs during CMI treatment (n = 25) were not significantly different from that at week 5, although some individuals developed or resolved specific ECG changes. CONCLUSION: CMI and DMI both produced ECG changes typically reported for tricyclic antidepressants, and they differed on specific ECG changes. Changes in ECG measures for individuals from short to long term suggest that continued monitoring is required.

Adolescent↗
PubMed1997

Predicting desipramine levels in children and adolescents: a naturalistic clinical study.

OBJECTIVE: To determine the predictability and stability of desipramine (DMI) concentrations in a clinically treated sample of children, estimating the risk of developing potentially toxic DMI levels at a higher dose after a most recent level in a clinically acceptable range. METHOD: Subjects were 90 consecutive psychiatrically referred children and adolescents treated with DMI with at least two assays of serum DMI concentrations (462 pairs). Assay data were analyzed after log transformation and linear regression. RESULTS: Despite wide between-patient variability in serum DMI levels at the same dose, future within-subject DMI blood levels were highly predictable from knowledge of current levels, current dose, and the future dose. When the DMI serum level was 200 to 300 ng/ml, there was a 7.0% risk for subsequent levels at the same dose to exceed 300 ng/mL, but potentially toxic levels above 500 ng/mL were very infrequent (1.7%). CONCLUSIONS: Although the results of this naturalistic clinical study may not generalize to other situations, the results indicate a reasonable stability, predictability, and safety of DMI levels in individual psychiatrically treated children that result from clinically chosen dose changes.

Adolescent↗
PubMed1999

Desipramine clearance in children and adolescents: absence of effect of development and gender.

OBJECTIVE: To examine the influence of development and gender on the pharmacokinetics of desipramine (DMI) in the pediatric population. METHOD: DMI pharmacokinetic parameters were calculated from 407 routinely drawn, dose- and weight-normalized serum concentrations in 173 youths receiving DMI (90 children, 83 adolescents; 29 were female, 144 were male). RESULTS: Mean pharmacokinetic parameters for the entire population included dose (3.78 +/- 1.51 mg/kg), weight- and dose-normalized serum concentration (45.41 +/- 47.39 [micrograms/L]/[mg/kg]), and DMI clearance (0.68 +/- 1.51 [L/kg]/hr). No between-group differences for children and adolescents were detected in dose (child, adolescent) (3.73 +/- 1.40 mg/kg, 3.83 +/- 1.68 mg/kg), weight- and dose-normalized serum concentrations (44.52 +/- 39.6 [micrograms/L]/[mg/kg], 46.34 +/- 34.89 [micrograms/L]/[mg/kg]; p = .62), and clearance (0.680 +/- 0.890 [L/kg]/hr, 0.695 +/- 1.05 [L/kg]/hr; p = .103). No between-group gender differences were detected in dose (male, female) (3.83 +/- 1.55 mg, 3.39 +/- 1.84 mg), weight- and dose-normalized serum concentrations (45.15 +/- 37.76 [micrograms/L]/[mg/kg], 47.14 +/- 34.96 [micrograms/L]/mg/kg]; p = .720), and clearance (0.699 +/- 0.89 [L/kg]/hr, 0.606 +/- 0.535 [L/kg]/hr; p = .390). CONCLUSIONS: These results suggest that age and gender do not significantly influence DMI clearance or dose-normalized serum concentrations in the pediatric population.

Adolescent↗
PubMed1999

Cardiovascular effects of desipramine in children and adults during exercise testing.

OBJECTIVE: In light of recent reports of sudden death in children being treated with desipramine (DMI), 3 of which were associated with physical exercise, the authors examined the effects of DMI on exercise in children and adults before and during DMI treatment. METHOD: Before treatment, 22 subjects (9 children, 13 adults) participated in a graded treadmill exercise test. Outcome measures included exercise tolerance, cardiovascular, and electrocardiographic parameters at progressive intensity levels and serum norepinephrine (NE) levels before and after exercise testing. Subjects were then treated with DMI, titrated to an average DMI dosage of 3 mg/kg, and underwent repeated exercise testing. RESULTS: DMI treatment was associated with a significant elevation of circulating NE levels in the pre-exercise assessment. Exercise tolerance was not affected by DMI, and blood pressure and heart rate effects were modest. The cardiovascular impact of DMI treatment was similar in children and adults. One 31-year-old subject exhibited a brief episode of ventricular tachycardia associated with exercise during DMI treatment. CONCLUSIONS: DMI has only minor effects on the cardiovascular response to exercise, and these effects do not appear age-related. However, DMI may increase the risk of exercise-associated arrhythmias in rare individuals.

Adolescent↗
PubMed1999

Effects of desipramine on autonomic input to the heart.

OBJECTIVE: To examine the impact of age on the effects of desipramine (DMI) on autonomic input to the heart. METHOD: Twenty-four-hour electrocardiograms were obtained from 42 subjects, aged 7 to 66 years, while off and on DMI. To obtain measures of autonomic input to the heart, heart rate variability was assessed via spectral analysis of RR interval variability. RESULTS: DMI treatment was associated with a significant increase in 24-hour mean heart rate and significant decreases in RR interval variability in all spectral bands, including in the high-frequency band, which provides a measure of parasympathetic input to the heart. RR interval variability was greater in younger individuals both off and on DMI. CONCLUSIONS: DMI treatment was associated with a marked decline in RR interval variability, indicating that DMI affects autonomic input to the heart. Specifically, DMI reduced parasympathetic input, which, in theory, may increase vulnerability to arrhythmias. However, the magnitude of DMI's impact on RR interval variability did not vary with age.

Adolescent↗
PubMed1997

Concurrent treatment of nonresistant major depression with desipramine and lithium: a double-blind, placebo-controlled study.

The objective of this study was to compare the onset, rate of antidepressant (AD) response, and treatment outcome of depressed patients treated for 5 weeks with either the concomitant administration of the tricyclic AD desipramine (DMI) and lithium carbonate (Li) or with DMI alone. In this double-blind, placebo-controlled study, 31 nonpsychotic, mild to moderately depressed outpatients (DSM-III-R unipolar or bipolar major depression) were randomly assigned to 5 weeks of treatment with DMI plus Li (N = 16) or DMI plus placebo (N = 15). Drug dosages were adjusted to achieve therapeutic plasma levels. Clinical state was rated weekly by the Hamilton Rating Scale for Depression, the Clinical Global Impression Scale, a Visual Analogue Self-Report Scale, and an adverse-effect form. Twenty-seven patients completed the study, 12 in the DMI-Li group and 15 in the DMI-placebo group. Four patients dropped out due to adverse events, all from the DMI-Li group. Both groups responded well to treatment, without a significant difference between them in the rate of response of final outcome. Sixty-seven percent (10/15) of the patients taking DMI only and 75% (9/12) of the patients taking DMI plus Li met our response criteria. The combination of DMI and Li was associated with significantly more adverse effects than DMI alone. Concurrent treatment with Li did not demonstrate an enhancement of either DMI's efficacy or its onset of action in these patients, suggesting that this strategy may not confer any additional benefit compared with DMI alone in mild to moderately depressed patients who are not preselected for nonresponse to an AD during their current depressive episode.

Adult↗