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The authors describe a case in which flupenthixol decanoate and imipramine were co-administered to a patient with schizophrenia, resulting in extremely high levels of imipramine and its metabolite, desipramine. The literature on the co-administration of neuroleptics and antidepressants is reviewed and guidelines for limiting possible iatrogenic effects of the combination are suggested.
Twenty-four outpatients meeting DSM-III-R criteria for major depression were assigned to group behavioral-cognitive therapy either with or without antidepressant medication (imipramine). Eighteen patients completed 15 weekly sessions of treatment. Equivalent improvement was observed in both regimens after treatment. The results essentially maintained at six months follow-up. This suggests that a group format of behavioural-cognitive therapy is a viable therapeutic intervention for outpatients diagnosed as suffering from major depression. However, the addition of imipramine to group behavioural-cognitive therapy did not enhance the outcome.
Steady-state serum concentrations of imipramine (IMI), its demethylated metabolite desipramine (DMI), and the active, hydroxylated metabolites, 2-hydroxy-imipramine (2-OH-IMI) and 2-hydroxy-desipramine (2-OH-DMI) were monitored in 126 psychiatric patients receiving IMI therapy. DMI and 2-OH-DMI concentrations were determined in a similar group of 61 DMI-treated patients. Although significant correlations exist between hydroxy metabolite and precursor concentrations, considerable variability was also found. Mean (+/- SD) ratios for the IMI patients were: 2-OH-IMI:IMI = 0.27 (+/- 0.19) and 2-OH-DMI:DMI = 0.56 (+/- 0.30). The ratio of DMI:IMI for males and 2-OH-DMI:DMI for females decreased with age (r = -0.42 and -0.32, respectively, p less than 0.01). Variable metabolite concentrations and the uncertainty of their relative psychoactivity may contribute to the difficulties in relating antidepressant efficacy to serum concentrations of the administered IMI or DMI.
Among the various medications that have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH) are the tricyclic antidepressants. A 69-year-old man admitted for treatment of a depressive disorder that had not responded to trazodone was prescribed imipramine. Twenty-two days after initiation of therapy, the patient developed hyponatremia. The patient also had depressed serum osmolality and elevated urine sodium concentrations consistent with SIADH. With the discontinuation of imipramine, fluid restriction, and several doses of furosemide, normal serum sodium concentrations were attained. As antidepressant therapy was indicated, doxepin was selected. The patient maintained normal electrolyte values and water balance over the next two months of follow-up. No reports of doxepin-related SIADH were found in the literature; therefore, this agent may be considered as an alternative therapy in patients developing SIADH during antidepressant drug therapy.
A double-blind, controlled study was carried out in 20 patients diagnosed as suffering from depressive disorder according to DSM-III criteria to compare the effectiveness and tolerability of fluvoxamine, a serotonin re-uptake inhibitor, with that of imipramine. Patients were allocated at random to receive one or other drug for a period of 4 weeks, dosage starting at 50 mg for the first 3 days and increasing to 100 mg daily for a further 3 days. Dosage was continued at this level for the remainder of the trial but was increased, if necessary, to 150 mg daily in two divided doses. Assessments of symptom severity were made on entry and response after 1, 2 and 4 weeks of treatment using the Hamilton Rating Scale for Depression, the Clinical Global Impression and a Visual Analogue Scale. Tolerability was assessed using the Dosage Record and Treatment Emergent Symptom Scale. The results showed that at the end of the trial there was a significant reduction in depressive symptoms severity in both groups and that fluvoxamine was significantly more effective than imipramine in reducing suicidal ideas and anxiety/somatic symptoms. Both drugs were relatively well tolerated but the side-effect profiles were different, being mainly of the anticholinergic type with the tricyclic and gastro-intestinal with fluvoxamine.
A method of reviewing a series of clinical trials by extracting the basic data in the form of 2 x 2 tables and analysing these by Fisher's two-tailed Exact Test is described, and illustrated by published imipramine-placebo trials. The results suggest that the benefit of this drug in patients with endogenous depression who have not become institutionalized is indisputable, and that further drug-placebo trials in this condition are not justified. Two of the three trials of imipramine in neurotic depression gave results showing significant improvement. Possible explanations of the apparent failure of this drug in groups of patients with undifferentiated depression are discussed.
Forty-five agoraphobic out-patients were randomly assigned to treatment with imipramine or placebo, and also to brief therapist-aided exposure or relaxation. All patients did systematic self-exposure homework and recorded this in a diary. Forty of these patients were followed-up two years later with self-ratings and ratings by interviewers blind to their treatment conditions. About two-thirds of the patients remained improved or much improved in their phobias, with no significant difference between any of the four treatment conditions. Spontaneous panics also remained improved. The absence of an imipramine effect may reflect the lack of initial dysphoria (anxiety-depression) in this sample compared with other studies where drug-effects have been found. The post-treatment superiority (evident at week 28) of patients who had therapist-aided exposure was no longer present at the two-year follow-up; the others had caught up, presumably because of their self-exposure homework.
In a 6-week double-blind trial, the efficacy of imipramine and high dose phenelzine were compared in the treatment of Major Depression with Melancholia, and Dysthymic Disorder (DSM-III). Both drugs were found to be equally efficacious in the treatment of 32 patients suffering from Major Depression. In 32 Dysthymic patients, phenelzine in high doses was found to be superior to imipramine. The clinical implications of these findings are discussed.
The Cross-National Collaborative Panic Study, Phase Two, compared alprazolam with imipramine and with placebo in a sample of 1168 randomly assigned subjects. The study, conducted at 12 centres, assessed clinical change over eight weeks of double-blind drug treatment. Improvement occurred with alprazolam by week 1 and 2, and with imipramine by week 4. By the end of week 8, however, the effects of the two active drugs were similar to each other, and both were superior to placebo for most outcome measures.
Effects of lyophilization and storage of liver 9,000xg supernatant fraction on the activity of drug metabolizing enzymes in some species of animals were studied. Imipramine metabolizing enzyme activity and the content of cytochrome P-450 were stable for, at least, one month without any loss of the activity when lyophilized liver 9,000xg supernatant fraction of some animal species, i.e., rat, mouse, guinea pig, rabbit and dog, was stored under reduced pressure in a deep freezer (-20 degrees C). There were no differences of imipramine metabolism between lyophilized liver 9,000xg supernatant fraction which was kept in a deep freezer for one month and a fresh fraction which was prepared immediately before determinations of the enzyme activity and cytochrome P-450. The data presented here indicated that the lyophilized preparation of the liver 9,000xg supernatant as well as the fresh preparation can be used for the determination of the drug metabolizing enzyme activity.
The concentrations of 11 amino acids were determined in 9 regions of the rat brain following the acute administration of the antidepressant drugs imipramine and Org. GB94, and chlorpromazine. The amino acids were determined as their dansyl derivatives. Unequivocal changes were only found in the concentrations of gamma-aminobutyric acid, alanine, asparagine + glutamine, glycine and taurine in some brain regions. Chlorpromazine produced the greatest change in these amino acids. Imipramine and Org. GB94 had qualitatively different effects on the concentrations of the amino acids in the 9 brain regions.
Pigeons were trained to perform simultaneous, two-color matching to sample under a multiple fixed-ratio fixed-interval schedule of food presentation. The sequence terminating with a peck on the matching key (a "match") was treated as a unit, analogous to a single key peck in conventional schedules. Except for intermittent reinforcement of matches, no consequent stimulus distinguished matches from mismatches (sequences terminating with pecks on the nonmatching key). The pattern of matches during nondrug sessions resembled that of simpler operants maintained by similar schedules. Matches increased in rate toward the end of both components; mismatch rates increased more slowly. Imipramine increased the rate of mismatches, disrupted schedule patterning, and lowered accuracy in a dose-dependent fashion. Chlorpromazine lowered the overall rate of matches but affected schedule patterns and accuracy less than imipramine. The types of errors during drug sessions were not systematically related to the types of errors that appeared during nondrug sessions. Stimulus control was evaluated for each of the four possible color configurations and was found to be by the entire configuration of colors, not simply by the color of the sample.
Perceptual-motor effects of imipramine and methylphenidate were evaluated in a double-blind study of 47 hyperactive children. No effects were found for imipramine, although methylphenidate improved performance on several tests. Improvement due to methylphenidate was not related to base-line scores. A discriminant function was computed to compare baseline perceptual-motor scores of the hyperactive and 41 normal children. Only half of the hyperactive children were clearly discriminated from normal children by the discriminant function. The digit-span test, which was not sensitive to methylphenidate, effectively discriminated hyperactive from normal children.
The effects of the tricyclic antidepressant imipramine were evaluated in a study of 9 children with Attention Deficit-Hyperactivity Disorder. The study was double-blind, placebo-controlled, with three drug conditions, low, medium, and high doses. The focus was on neuropsychological drug effects. Imipramine exerted negative dose-response effects on motor performance (motor speed, motor pursuit), while it improved hyperactive behavior and attention and raised the heart rate slightly.
The tricyclic antidepressant imipramine was instilled directly onto the lung surface of experimental rats in specific low doses (0.025 - 0.60 mg/kg body weight) and the animals were sacrificed at time intervals from 2 - 21 days after a single instillation. Such treatment caused changes almost exclusively confined to the alveolar surface. Alterations were induced in the free cell numbers and lung lavage protein levels while alveolar lipid and pulmonary surfactant levels were elevated. All such changes could be considered indicative of a mild toxic reaction. Imipramine at these low dose levels appeared specific in its effect in promoting surfactant accumulation in the absence of other toxic effects.
The inhibitory effect of amitriptyline and imipramine on human sperm motility was measured in vitro with a transmembrane migration method. The EC50 for amitriptyline and imipramine were 170 microM and 160 microM respectively. They were more potent than any other drug that had been tested on this pharmacological model. Transmembrane migration method was less sensitive than turbidimetric method to detect the sperm immobilizing effect of drugs.
Specific binding of [3H]-imipramine in the rat suprachiasmatic nuclei, occipital cortex and caudate putamen underwent significant and replicable changes throughout 24 hr under a light-dark cycle or under constant conditions. Daily variations were also found in the medial and dorsal raphe nuclei and the lateral hypothalamus. Methamphetamine, a psychoactive drug with marked effect on circadian rhythms in physiological and hormonal parameters and adrenergic receptors, did not have any significant effect on imipramine binding rhythms in eight discrete brain regions. Thus a drug known to reduce serotoninergic neurotransmission did not change characteristics of the modulatory binding site related to serotonin uptake.
Sleep deprivation (SD) modified the circadian rhythm of specific high affinity serotonin (5-HT) binding to rat brain membranes. In control rats a 24-hr rhythm was evident with a trough at 1000-1200 and a nadir at 0000. During the last 26 hr of a 49 hr SD period, trough and peak values were delayed by 4-6 hr. The 24-hr mean binding was significantly (P less than 0.001) different from that of controls. If sleep deprivation was followed by recovery sleep (RS), the normal rhythm of 5-HT binding was obtained already within 1 hr after SD. The effects of SD and RS were ascertained by plasma ACTH and corticosterone assay. No significant change in the hormone rhythms were observed through the mean plasma level of ACTH and corticosterone were enhanced to about 180 and 150%, respectively. Chronic treatment with the antidepressant imipramine resulted in a decrease of the 24-hr mean 5-HT binding by about 50% and a 2-hr delay of peak and trough values. Imipramine treatment decreased the peak value of 5-HT concentration at 1000 to about 65% and appears to abolish the rhythm of 5-HT concentration.