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PubMed1995

Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6.

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine identical to norfluoxetine > or = sertraline > or = fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs. In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6. Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines, and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and beta-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an approximately 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting (approximately 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an approximately 3-fold increase in plasma desipramine concentration. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest (approximately 30%) elevation in plasma desipramine concentrations. Coadministration of fluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steady-state] with imipramine or desipramine resulted in approximately 3- to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine (approximately 3- to 4-fold increase in AUC) through inhibition of CYP3A3/4, CYP1A2, and CYP2C19. Thus, the extent of the in vivo interaction between the SSRIs and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems, especially if one takes into account pharmacokinetic factors.

Animals↗
PubMed1983

Imipramine metabolites in blood of patients during therapy and after overdose.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.

Adult↗
PubMed2006

Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade.

Parietal and occipital cortices, while densely innervated by noradrenalin 2 (NA) projections, possess a comparatively sparse dopamine 2 (DA) innervation, even sparser than the prefrontal cortex. We previously reported that reboxetine and desipramine, two selective norepinephrine transporter (NET) blockers, at doses that maximally increase DA in the prefrontal cortex, do not increase DA in the parietal and occipital cortices. In the present study, we performed a full dose-response study of the effect of systemic reboxetine and desipramine on DA and NA in dialysates from the parietal and occipital cortices. Seven doses of reboxetine (0.1, 0.25, 0.5, 1.0, 2.5, 5.0 and 10 mg/kg) and four doses of desipramine (0.25, 1.0, 2.5 and 5.0 mg/kg) were tested. Reboxetine and desipramine differentially affected dialysate DA as compared with NA. Reboxetine increased DA maximally by about 100% after doses of 0.25-0.5 mg/kg and showed a bell-shaped dose-response function in both areas; desipramine did not affect DA in the parietal cortex and increased it in the occipital cortex only at 2.5 mg/kg. NA was maximally increased by 275% by 0.5-2.5 mg/kg reboxetine and by about 300% by 5.0 mg/kg desipramine with a more linear dose-response curve. The mechanism of peculiar dose-response function of dialysate DA after reboxetine and desipramine was further investigated by testing the effect of drugs on dialysate DA and NA under alpha(2) receptor blockade. Under local perfusion of the occipital cortex with idazoxan, an otherwise ineffective dose of reboxetine and desipramine (5 mg/kg) became effective in raising extracellular DA. In contrast, the effect of reboxetine on NA was potentiated, while that of desipramine was not affected. These results suggest that, in the parietal and occipital cortices, extracellular NA, raised by NET blockade, exerts a preferential inhibitory influence on DA release by acting on local alpha(2) receptors, thus accounting for the bell-shaped feature of the dose-response function of drugs on dialysate DA in these areas.

Adrenergic Uptake Inhibitors↗
PubMed1996

Antidepressant pharmacotherapy and the treatment of depression in patients with severe traumatic brain injury: a controlled, prospective study.

BACKGROUND: Untreated or poorly treated depression in patients who suffer from traumatic brain injury can result in greater functional disability and prolonged or ineffective hospital and rehabilitation stays. Literature available on the pharmacologic treatment of depression after traumatic brain injury is scarce. This study investigated in a controlled and prospective manner the use of desipramine, a tricyclic antidepressant, in a series of patients with severe traumatic brain injury. METHOD: Ten patients with severe traumatic brain injury and long-standing depression, as diagnosed by DSM-III-R criteria, were admitted to the study because of the intention to be treated with antidepressants. They were randomly assigned to blindly start on either desipramine treatment (N = 6) or placebo lead-in (N = 4). Patients starting with desipramine stayed on that drug; patients starting with placebo lead-in were blindly crossed over to desipramine after 1 month if there was no significant improvement demonstrated by DSM-III-R criteria. All rating clinicians, physicians, and patients were blind to actual treatment and any ratings data. DSM-III-R evaluations were done monthly. An affect/mood scale was done every 2 weeks. RESULTS: Of all patients evaluable using the DSM-III-R, 6 (86%) of 7 demonstrated resolution of depression and depressed mood during desipramine treatment. (Three received desipramine throughout the study; 3 others started taking placebo and crossed over to desipramine,) One patient refused evaluation on DSM-III-R throughout; 2 patients, both on desipramine, dropped out because of adverse effects (seizure, mania). In addition, there was statistically significant (p = .001) improvement over time and different rates of improvement over time in the treated and untreated groups for the affect/mood scale data. CONCLUSION: Results from this small study, utilizing a blinded, placebo lead-in design appear to (1) demonstrate the clinically significant effectiveness of desipramine in treating long-standing depression in a series of patients with severe traumatic brain injury, as rated with DSM-III-R criteria; (2) show statistically significant improvement on the affect/mood scale data, favoring the treated versus untreated (placebo lead-in) group.

Accidents, Traffic↗
PubMed1994

One-year follow-up of psychosocial and pharmacologic treatments for bulimia nervosa.

BACKGROUND: This study examined the outcome 1-year posttreatment of the use of desipramine, cognitive-behavioral therapy (CBT), and their combination in the treatment of bulimia nervosa. METHOD: Sixty-one patients meeting DSM-III-R criteria for bulimia nervosa were randomly assigned to one of five groups--desipramine (withdrawn at 16 or 24 weeks), CBT (18 sessions), or the combined treatment (18 sessions of CBT plus desipramine withdrawn at 16 or 24 weeks)--and were followed to 1-year posttreatment. RESULTS: At 1-year follow-up, both the combined 24-week treatment and CBT alone were significantly superior in reducing binge eating to desipramine given for 16 weeks. The combined treatment was also superior to 16 weeks of desipramine in reducing emotionally driven eating and dietary restraint. Only 18% (2 of 11) of those receiving 16 weeks of desipramine were free of binge eating and purging at follow-up compared with 78% (7 of 9) of those receiving the combined 24-week treatment. The other groups fell between these two extremes. CONCLUSION: With the exception of the group treated for 16 weeks with desipramine alone, maintenance of improvement appeared satisfactory with all the treatments. Since the poorest results were found with 16 weeks of desipramine treatment, this study suggests that desipramine should be continued for at least 24 weeks either alone or combined with CBT. The broadest gain in reducing the psychopathology associated with bulimia nervosa was found with the combined 24-week treatment.

Adolescent↗
PubMed2004

Brain-derived tumor necrosis factor-alpha and its involvement in noradrenergic neuron functioning involved in the mechanism of action of an antidepressant.

The present study documents a role for brain-derived tumor necrosis factor-alpha (TNF) in the mechanism of action of the antidepressant drug desmethylimipramine (desipramine). To establish this role, field stimulation and superfusion of rat hippocampal slices was employed to investigate the regulation of norepinephrine (NE) release by TNF. Chronic desipramine administration transforms TNF-mediated inhibition of NE release to facilitation, dependent upon alpha2-adrenergic receptor activation. Chronic i.c.v. microinfusion of polyclonal TNF antibody (pTNF-Ab) similarly transforms TNF inhibition of NE release to facilitation. To determine whether this transformation is due to desipramine-induced inhibition of TNF bioactivity in the brain, rats were i.c.v. microinfused with recombinant rat TNF (rrTNF) for 14 days, either alone or with simultaneous i.p. desipramine administration. TNF regulation of NE release in hippocampal slices isolated from these rats was compared with slices isolated from rats chronically administered desipramine alone. Although simultaneous microinfusion of rrTNF with chronic desipramine administration prevents the transformation induced by desipramine, microinfusion of rrTNF enhances TNF inhibition of NE release. These cellular events correspond to changes in immobility, analyzed by the forced swim test (FST). Intracerebroventricular microinfusion of rrTNF increases the duration of immobility of rats in the FST, compared with rats microinfused with aCSF. Desipramine administered chronically decreases immobility duration, which is mimicked by i.c.v. microinfusion of pTNF-Ab and prevented by simultaneous i.c.v. microinfusion of rrTNF. Thus, i.c.v. microinfusion of rrTNF with concomitant desipramine administration opposes decreases in neuron-associated TNF levels, required to transform presynaptic sensitivity to TNF, which is necessary for the drug to be efficacious.

Animals↗
PubMed1995

Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts.

In myocardial ischemia, nonexocytotic noradrenaline release has been identified as underlying mechanism of ischemia-evoked noradrenaline release. Nonexocytotic noradrenaline release can be suppressed by inhibitors of the neuronal noradrenaline carrier (uptake), such as desipramine. Utilizing this pharmacological intervention the role of local noradrenaline release in the genesis of ischemia-induced ventricular arrhythmias was studied. Regional ischemia was induced in rat isolated perfused hearts by ligature of the left anterior descending coronary artery, and the venous effluent obtained during the first 2 min of reperfusion was used to measure the release of endogenous noradrenaline by high-performance liquid chromatography methods. Coronary occlusion caused ventricular fibrillation in a well reproducible manner with an incidence of 70 to 80% during a 30 min observation period. Blockage of uptake1 by desipramine decreased the occurrence of ischemia-induced ventricular fibrillation to 60% (0.01 mumol/l) or 20% (0.1 mumol/l), and ventricular fibrillation was completely suppressed by 1 mumol/l desipramine. Likewise, desipramine (0.01-1 mumol/l) concentration-dependently reduced endogenous noradrenaline release during 30 min of regional myocardial ischemia. Nisoxetine, a structurally unrelated inhibitor of uptake1, also suppressed ischemia-evoked ventricular fibrillation. In contrast to its antifibrillatory effect during regional myocardial ischemia, desipramine precipitated arrhythmias when ventricular fibrillation was induced by perfusing normoxic hearts with exogenous noradrenaline. Combination of desipramine (0.1 mumol/l) with exogenous noradrenaline (0.01 to 1 mumol/l) increased the incidence of ventricular fibrillation compared to noradrenaline perfusion alone. Under these conditions, uptake1-blockade is known to increase the extracellular concentration of the perfused noradrenaline. Finally, in the isolated, spontaneously beating papillary muscle of the left rat heart, desipramine (0.1 and 1.0 mumol/l) had no effect on the upstroke velocity of action potentials, the action potential duration and the effective refractory period. In conclusion, the findings demonstrate that nonexocytotic noradrenaline release is an important mediator of ischemia-induced ventricular fibrillation in isolated hearts of the rat. It is also documented that uptake1 inhibitors such as desipramine reveal their effects on ventricular fibrillation secondary to their action on transmembrane noradrenaline transport.

Adrenergic Uptake Inhibitors↗
PubMed1986

Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics.

Seventeen hospitalized patients (age 39-66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40-637 nmol/l for imipramine, 49-1148 nmol/l for desipramine and 89-1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548-910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50-400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.

Adult↗
PubMed2006

Antidepressant-induced undesirable weight gain: prevention with rimonabant without interference with behavioral effectiveness.

Antidepressant pharmacotherapy has dramatically improved the quality of life for many patients. However, prolonged use may induce weight gain, resulting in enhanced risk for treatment noncompliance. Cannabinoid CB(1) receptor antagonists decrease food intake and body weight, but may also affect mood. We investigated in female Sabra mice first, whether acute treatment with the cannabinoid receptor antagonist rimonabant (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, SR141716, 5 mg/kg) interfered with the tricyclic antidepressant desipramine (15 mg/kg) or the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) in the Porsolt forced swimming test. Second, whether chronic treatment (3 months) with desipramine (5 mg/kg) enhanced weight gain and whether cotreatment with rimonabant (2 mg/kg), prevented the excessive weight gain, while retaining antidepressant effectiveness. Motor activity and anxiety-like behavior were also investigated. The acute studies indicated that rimonabant did not influence 'antidepressant' activity of desipramine or fluoxetine. In the chronic studies, desipramine enhanced weight gain, despite the observation that the injection procedure reduced weight gain. The enhanced weight gain continued at least 35 days after treatment ended. Rimonabant reduced weight gain to which no tolerance developed and which persisted at least 30 days beyond treatment. Mice cotreated with rimonabant and desipramine had body weights closer to controls or to those receiving rimonabant alone than to those treated with desipramine alone. The antidepressant effects of desipramine were maintained throughout treatment; this was not altered by the chronic rimonabant treatment at any time, although rimonabant together with desipramine transiently enhanced anxiety-like behavior. These observations suggest that combined treatment with antidepressants and cannabinoid CB(1) receptor antagonist to prevent undesirable weight gain, should be further investigated.

Analysis of Variance↗
PubMed1998

The combined effects of chronic ethanol/desipramine treatment on beta-adrenoceptor density and coupling efficiency in rat brain.

Both ethanol and desipramine influence beta-adrenoceptor regulation. We reported previously that ethanol partially counteracted desipramine's effects on beta-adrenoceptor. Previous studies utilized beta-adrenoceptor radioligands that also bind to 5-HT1B receptors, thus, changes in 5-HT1B receptors could have confounded the results. The effects of chronic ethanol, desipramine and ethanol/desipramine treatment on beta-adrenoceptor coupling efficiency to Gs protein in rat brain were examined using 125I-iodocyanopindolol after blocking binding to 5-HT1B receptors. In the frontal cortex, ethanol uncoupled beta-adrenoceptor from GS. Desipramine decreased beta-adrenoceptor density, particularly in the high-conformational state, with no effect on coupling. In combined treatment, desipramine prevented ethanol-induced uncoupling. In the hippocampus, desipramine enhanced beta-adrenoceptor coupling, but ethanol had no effect. In combination with desipramine, ethanol enhanced desipramine-induced decrease in beta-adrenoceptor density in the high-conformational state, but uncoupled beta-adrenoceptors, an effect not observed with ethanol alone. These results suggest a complex interplay between ethanol and antidepressants in modulating beta-adrenoceptor function.

Adrenergic Uptake Inhibitors↗
PubMed1988

Characterization of the inhibitory effect of some antidepressant drugs on the outward transport of norepinephrine in the ischemic myocardium.

The noradrenergic amine carrier has an important role in mediating the local release of norepinephrine (NE) during myocardial ischemia. The effects of the antidepressant or putative antidepressant drugs desipramine, 2-hydroxy desipramine, nisoxetine, (S)-oxaprotiline and (R)-oxaprotiline with respect to this release mechanism were investigated in the isolated rat heart submitted to total stop-flow ischemia and subsequent reperfusion. During the reperfusion phase a massive efflux of NE was observed, which was reduced in a concentration-dependent manner in the presence of the antidepressant drugs. The potency (pIC50) of the antidepressants in inhibiting the ischemia-induced NE release varied between 9.16 (desipramine) and 6.17 [(R)-oxaprotiline]. On the other hand, lidocaine (10 microM) or clonidine (1 microM) did not reduce the magnitude of the NE efflux. No attenuation in NE efflux could be detected when desipramine (0.1 microM) was present only during the reperfusion period. During repeated periods (3 x 20 min) of ischemia, desipramine (0.1 microM) reduced markedly the loss of NE. In another experiment in the isolated guinea pig heart, desipramine (0.1 microM) was also found to attenuate the ischemia-induced mobilization of NE to the same significant extent as in the isolated perfused rat heart. Chronic treatment (3 weeks) of rats with desipramine as well as acute administration of desipramine to rats (2 hr before the initiation of perfusion) caused a pronounced reduction in the ischemia-induced release of NE in the isolated perfused heart. In conclusion, these experiments strongly suggest that a major part of the ischemia-induced release of NE is mediated by the amine carrier associated with the noradrenergic nerve terminal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗