Dose Of Desipramine Research Articles

Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies

The tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in adult depression. Animal studies comparing the effects of DMI in juveniles and adults are complicated by age-related variations in elimination rates. Thus, different dosing regiments are needed to achieve similar brain drug levels in juvenile and adult rats. We compared the half-life of DMI as well as the brain and serum concentrations of DMI and its active metabolite desmethyldesipramine in juvenile and adult rats after various drug administration paradigms. After acute i.p. administration DMI is eliminated from the brain more slowly in postnatal day (PND) 21 and 28 rats as compared to adults. After chronic i.p. administration (for 4–5 days between PND 9 and 28), lower doses of DMI are needed with juvenile rats to obtain the same brain DMI concentrations as adults. By contrast, 2 weeks of continuous drug delivery (minipump) to PND 21–35 and adult rats result in similar brain DMI concentrations. Thus, the pharmacokinetic properties of DMI varies with the age of the animal and dosing of DMI and needs to be carefully adjusted in order to have appropriate brain levels of the drug.

Differential α2‐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.

Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl

In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects. Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose. Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet. This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.

Behavioral and biochemical effects of single dose of desipramine are time-dependent

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based.

Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers

In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study. This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir. Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer. Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.

Clinical Response to Tricyclic Antidepressants in Functional Bowel Disorders is not Related to Dosage

As shown in the per protocol analysis of a recent randomized, controlled trial, when tolerated, Desipramine (DES) is effective over placebo (PLA) in treating moderate-to-severe functional bowel disorders (FBD). Clinical experience suggests that the benefit from tricyclic antidepressants (TCA) in FBD can be achieved at doses lower than those used to treat major depression. Within psychiatry, when using higher dosage of TCAs, plasma levels can be used to adjust daily dosage to optimize a treatment response. However, in FBD, it is not known whether plasma levels at the lower dosage are similarly related to a clinical response. To determine in treating FBD, whether DES blood levels or dose taken can predict a clinical response. As part of a study of 12 wk of antidepressant and psychological treatment in 431 patients with FBD at UNC and U of Toronto, we studied those participants who completed treatment (per protocol analysis) taking DES (N = 97, dose 50-150 mg/day) or pill placebo (PLA) (N = 55 1-3 pills/day). The primary outcome measure was defined as a composite score (Satisfaction with Treatment, McGill Pain Questionnaire, Global Well-being, and IBS-QOL). The composite score was correlated with: (i) DES plasma levels at week 6, and (ii) number of pills taken over the duration of the 12-wk treatment period. In addition, we also compared DES dose with DES plasma levels. There was a modest correlation between mean DES dose at weeks 5 and 6 and DES blood level at week 6 (R = 0.2 p < 0.07). However, there were no significant correlations between the composite score either with DES dose or with DES blood levels. Detectable blood levels of DES are associated with a clinical response in FBD. However, with dosages up to 150 mg, there is no relationship between total dose or plasma level and the clinical response.

Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Background In-vitro data showed that febuxostat had no significant effect on CYP1A2, CYP2C9, CYP2C19 or CYP3A4 activity (Ki>100 μM), and a weak inhibitory effect on CYP2D6 (Ki=40 μM). Aim The effect of febuxostat on desipramine pharmacokinetics (PK) was evaluated. Methods A phase-1, two-period, crossover, double-blind study was conducted in 18 CYP2D6 extensive-metabolizer subjects. Each subject received a single 25 mg oral dose of desipramine (DES) after multiple oral dosing with febuxostat (FBX) 120 mg or placebo (PLA) once daily. Blood samples were collected to assess the PK of DES and 2-hydroxydesipramine (2-HD). Results The results are shown in the table below. The increase in total exposure to DES and the concomitant decrease in the 2-HD/DES AUC ratio suggest that the metabolism of DES to 2-HD via CYP2D6 was mildly inhibited. However, this effect was not considered to be clinically significant. The incidence of adverse events was similar between treatment regimens with the majority being mild and moderate in severity. Conclusion No dose adjustment is expected for CYP2D6 substrates when co-administered with febuxostat. Clinical Pharmacology & Therapeutics (2005) 77, P43–P43; doi: 10.1016/j.clpt.2004.12.059 Table 1. Mean±SD Plasma PK for DES and 2-HD, Point Estimates (PE) and Confidence Intervals (CI) Parameter DES + FBX DES + PLA PE (90% CI)1 1 Ratio of DES+FBX to DES+PLA 2 AUC Ratio: 2-HD/DES AUC ratio DES Cmax (ng/mL) 9.6 ± 3.5 8.4 ± 3.2 1.16 (1.10–1.23) AUC∞ (ng h/mL) 295 ± 194 263 ± 249 1.22 (1.11–1.35) 2-HD Cmax (ng/mL) 6.2 ± 2.0 6.6 ± 2.3 0.96 (0.90–1.02) AUC∞ (ng h/mL) 163 ± 30 166 ± 62 1.02 (0.93–1.11) AUC Ratio2 0.74 ± 0.40 0.88 ± 0.49 0.83 (0.76–0.91}

Ejaculation induces long-lasting behavioural changes in male rats in the forced swimming test: evidence for an increased sensitivity to the antidepressant desipramine

Copulation to exhaustion induces a sexual inhibitory state featured by a decreased motivation. Since diminished motivation is a key symptom of depression, we analysed if sexually exhausted animals showed increased levels of depressive-like behaviour in the forced swimming test (FST). Besides, sexual activity has been reported to have reinforcing properties. Thus, we analysed whether different levels of sexual activity modified the development of the behavioural despair in the FST. Finally, the effect of a sub-threshold dose of desipramine (DMI, 2.5 mg/kg) was evaluated in animals with different sexual conditions. Male adult rats were divided into: (a) naïve rats and (b) animals executing one intromission (1-INTR) or (c) one ejaculation (1-EJ) and (d) sexually satiated rats, classified as sexually responsive (R) and non-responsive (NR). No differences were found in immobility behaviour between sexually exhausted and naïve rats. In the pre-test sessions of the FST males attaining ejaculation (1-EJ, R and NR) had lower levels of immobility or showed a tendency towards such a diminution, while animals with sexual activity not involving ejaculation did not. Data suggest a “protective” effect of ejaculation against the development of depressive-like behaviour. Finally, the sub-effective dose of DMI produced an antidepressant-like action in all animals that ejaculated. In conclusion, sexual experience involving ejaculation modifies the behavioural expression of rats in the FST and their sensitivity to antidepressant drugs like DMI. Both responses reflect brain plastic changes induced by ejaculation.

Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study

Background Although several antidepressants are now available, all have limited efficacy and a delayed onset of action. The current study was undertaken as a proof of the concept that combining norepinephrine and serotonin reuptake inhibition would be more effective and act more rapidly than either drug alone. Methods Inpatients with nonpsychotic unipolar major depression and a Hamilton Depression Rating Scale (HAMD) score of at least 18 after 1 week of hospitalization without antidepressant medication were randomized to 6 weeks of treatment with fluoxetine (FLX) 20 mg/day, desipramine (DMI) adjusted to an adequate plasma level, or the combination of FLX 20 mg/day and DMI, given under double-blind conditions. Twenty-four-hour DMI levels were used to rapidly adjust DMI dose to achieve a therapeutic level and to anticipate the enzyme-inhibiting effects of FLX. Treatment-resistant patients were stratified. Patients were rated with the HAMD and the Montgomery-Asberg Depression Rating Scale (MADRS). Results Thirty-nine patients began treatment. One patient withdrew consent. The DMI–FLX combination was significantly more likely to result in remission on the MADRS than either FLX or DMI alone [53.8% vs. 7.1% and 0%, respectively; χ 2(2) = 13.49, p = .001]. The advantage for combined treatment was not explained by history of treatment resistance or by drug plasma concentrations. Rapid response, at 1 or 2 weeks, was neither statistically nor meaningfully greater with combined treatment. Conclusions This study supports the hypothesis that the combination of a noradrenergic and serotonergic agent is more likely to result in remission than either selective agent alone during a 6-week treatment period.

Is clinical response to tricyclic antidepressants in functional bowel disorders related to dosage?

Background: Desipramine (DES) is effective in treating moderate to severe Functional Bowel Disorder (FBD) over Placebo(PLA) as shown in the per protocol analysis of a Randomized, Controlled trial (Drossman at al, Gastroenterology 2003). Clinical experience suggests that benefit from antidepressants in FBD can be achieved at doses lower than those used to treat major depression. However, it is not known if monitoring the DES plasma levels in respect to dose adjustments or predicting clinical outcome in patients with FBD is clinically useful. Aim: To determine whether clinical response to DES is related to DES blood levels or number of pills taken. We report the correlation between DES dose and plasma level, DES dose and chnical outcome and DES plasma level and clinical outcome. Methods: As part of a study of antidepressant and psychological treatments in 431 patients with FBD at UNC or U of Ioronto, we studied those participants in the per protocol analysis taking DES (N = 95, dose 50-150 rag/day) or pill placebo (PLA) (N=55 1-3 pilLs/day). A composite outcome score (Satisfaction with treatment and McGill pain Questionnaires, global Well-being, and IBS-QOL) of clinical response was correlated with: 1)DES plasma levels at week 6 of a 12 week study, and 2) number of pills taken over sequential weekly periods (weeks 0-12,212,4-12,6-12,8-12,10-12) for participants taking DES and PLA. In addition, a correlation was obtained comparing number of DES pills taken with DES plasma levels. Results: 1) There is a correlation between DES blood levels at week 6 and DES dose during weeks 5&6 (R= 0.28, p<0.05); 2) There is no association between DES dose for any sequence of weeks or for DES blood levels at week 6 and the composite score at week 12; 3) These findings held for the DES group after those with non detectable blood levels were excluded; 4) There was no correlation between number of placebo pills taken with the composite score or blood levels (non detectable). Conclusions: For patients with moderate to severe FBD treated with DES, there is a modest correlation between DES dose and plasma level. However, the clinical response is not determined by the DES dose or plasma level. This supports the cresting wisdom that patients with FBD may respond even to low doses (e.g., 50 mg or less) of DES. Monitoring the DES plasma levels in patients with FBD appears not clinically useful unless toxicity is suspected Supported by N1H Grant R01DK49334.

Noradrenergic and Serotonergic Neuroendocrine Responses in Prepubertal, Peripubertal, and Postpubertal Rats Pretreated With Desipramine and Sertraline

To explore whether developmental status of neurotransmitter systems may affect response to antidepressant treatment. This study investigated whether younger animals, compared with mature animals, showed the same neuroendocrine response to challenge drug probes when pretreated with a serotonergic or noradrenergic antidepressant. Prepubertal, pubertal, and adult rats were pretreated with low- or high-dose sertraline or desipramine for 14 days. Animals were then challenged with a noradrenergic probe (clonidine for desipramine-treated animals) or a serotonergic probe (fenfluramine for sertraline-treated animals). The neurohormonal response of growth hormone to the clonidine challenge and prolactin to the fenfluramine challenge was then measured. In animals challenged with fenfluramine, the postpubertal control group showed a significantly higher prolactin response to fenfluramine than postpubertal animals pretreated with low- or high-dose sertraline. No differences were found in the pubertal or prepubertal group. In animals challenged with clonidine, there was a significant age by treatment interaction effect for the prepubertal group pretreated with high doses of desipramine (less growth hormone secretion) but not for the peri- or postpubertal groups. These data indicate neurodevelopmental factors may play a role in the functional physiology of neurotransmitter systems, which in turn may affect response to psychotropics.

Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: studies on the role of presynaptic alpha2-adrenoceptors.

Adaptive phenomena such as desensitization of autoreceptors are considered an important factor in the achievement of therapeutic efficacy of antidepressant drugs after chronic treatment. We have studied whether a chronic treatment with desipramine had a greater effect than a single dose on the extracellular concentrations of noradrenaline in the dorsal hippocampus. Administration of 10 mg/kg i.p. desipramine once daily for 14 days significantly raised the basal extracellular noradrenaline in the dorsal hippocampus 24 h but not 48 h after the last drug injection. A challenge dose of desipramine increased extracellular noradrenaline in rats treated chronically with vehicle and desipramine. The effect was significantly higher in rats treated chronically with desipramine 48 h but not 24 h after the last injection. An intraperitoneal administration of the alpha2-adrenoceptor agonist clonidine at the dose of 10 microg/kg significantly reduced extracellular noradrenaline in the control group but not in animals chronically treated with desipramine whereas 30 microg/kg clonidine produced a similar decrease in both groups. Three concentrations of clonidine (0.05, 0.5 and 1 microM) infused into the hippocampus significantly reduced extracellular noradrenaline to a similar extent in rats chronically treated with saline or desipramine. Fourty-eight hours after the last injection of the chronic treatment, [3H]RX-821002 binding to alpha2-adrenoceptors in the rat locus coeruleus measured by autoradiography was not significantly modified. A slight (17%) but significant decrease of neuronal uptake of [3H]noradrenaline was found in synaptosome preparations from dorsal hippocampus of rats chronically treated with desipramine, but this was likely due to a decrease in affinity. The results suggest that a repeated treatment with desipramine (10 mg/kg i.p. once daily for 14 days) facilitates its effect on extracellular noradrenaline in the dorsal hippocampus and induces adaptive changes probably involving desensitization of alpha2-adrenoceptors, with no changes in their density, on noradrenergic neurons in the locus coeruleus.

Desipramine binding to noradrenaline reuptake sites in cardiac sympathetic neurons in man in vivo

Noradrenergic reuptake blockade is a recognised mechanism of antidepressant action, but the extent of the blockade necessary for therapeutic effect is not known and plasma levels do not provide a guide to therapy. We report a method to assess noradrenaline reuptake blockade in vivo in man using [ 11C] meta-hydroxyephedrine and the multiple organs' coincidences counter. Eight healthy volunteers had two scans, one with tracer alone and one after preloading with desipramine 50–75 mg p.o. In all subjects, there was an increased washout rate of the radioligand from the heart following preloading ( t=4.38; P<0.003) as well as a decrease of the area under the [ 11C] meta-hydroxyephedrine time activity curve ( t=7.4; P=0.001). In one subject who had three doses of desipramine, the increase in washout rate was dose-dependent. In conclusion, [ 11C] meta-hydroxyephedrine in the multiple organs' coincidences counter gives a valid, low radiation method to assess noradrenergic reuptake blockade in the clinic.

Rapid, safe and stable antidepressant response with desipramine augmentation of serotonergic agents

Objectives: Partial response or non-response to serotonergic agents is not an unusual clinical phenomenon. The addition of tri-cyclic antidepressants is a recognized technique in overcoming this phenomenon. The specific objectives of this study were to 1) assess the efficacy of desipramine augmentation on mood 2) determine the onset of noticeable mood change after desipramine augmentation and 3) determine the side effects of the combination.Methods: The author reviewed the charts of patients who had desipramine augmentation as a result of partial or non-response to serotonergic antidepressants. Data were obtained on 1) duration of the depressive episode 2) dose and duration as well as degree of response to treatment with the serotonergic agent 4) dose of desipramine 5) side effects after desipramine augmentation 6) onset of noticeable mood change and 7) stability of response.Summary of Results: Nine patients had desipramine added to serotonergic agents. 5/9 were on nefazodone, 1/9 on fluoxetine and 3/9 we...

Effects of Antidepressants on Functional Recovery Following Stroke: A Double-Blind Study

Objective : To determine whether antidepressants that differ in their monoamine re uptake inhibitory effects—desipramine (noradrenergic), trazodone (relatively sero tonergic), and fluoxetine (selectively serotonergic)—differentially affect recovery from stroke associated with depression.Background: Animal models and limited studies in man show that noradrener gic agents enhance sensorimotor and visual recovery after brain injury, whereas sero tonergic agents impede such recovery.Methods: Twenty-four stroke rehabilitation inpatients meeting DSM3R crite ria for organic mood disorder with depression were randomized to receive desipramine (N = 13), trazodone (N= 6), or fluoxetine (N = 5). The initial and target doses of desipramine were 50 mg and 100 mg, respectively, fluoxetine, 10 mg and 20 mg, and trazodone, 50 mg and 100 mg.Results: The age, sex, interval post stroke, type and location of stroke, type of neurologic deficit, severity of depression (Hamilton Depression Scale [HDS]), func tional disability (...

Stimulation of immediate early gene expression by desipramine in rat brain

The stimulation of immediate early gene expression in brain and neuronal cell culture systems has been reported after various experimental paradigms such as chemiconvulsant-provoked seizures or specific drug applications. In particular, the induction of immediate early genes by adrenergic model substances has been demonstrated by several investigators. This report demonstrates that a single dose of desipramine (10 or 25 mg/kg), a classical tricyclic antidepressant drug acting on the adrenergic system, induced c-fos and zif268 expression in rat hippocampus without affecting c-jun. The observed immediate early gene response might reflect part of a signal transduction cascade involved in long-term neuroadaptive and behavioral changes after antidepressant drug treatment.

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression.

Desipramine modulates 3H-ouabain binding in rat hypothalamus.

We have previously shown that Na+, K(+)-ATPase activity in hypothalamus is increased after administration of an acute dose of desipramine, a noradrenaline uptake inhibitor (Viola et al., Cell Molec Neurobiol 9:263-271, 1989). In this report the same treatment (10 mg per kg) was applied to evaluate 3H-ouabain binding in rat brain sections by quantitative autoradiography. Results disclosed an increase in the number of ouabain binding sites in hypothalamus but not in cerebral cortex. Concomitantly, such acute DMI treatment enhanced K(+)-stimulated-p-nitrophenylphosphatase activity in hypothalamus membranes whereas it failed to modify cerebral cortex membranes. A direct interaction of DMI with the enzyme was ruled out since in vitro DMI is known to inhibit the enzyme. It may be speculated that DMI indirectly stimulates Na+, K(+)-ATPase through the increase in noradrenaline which acts in turn on the external phosphorylated site of the enzyme.

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression.

Inhibition by vitamin E of drug accumulation and of phospholipidosis induced by desipramine and other cationic amphiphilic drugs in human cultured cells.

1. Cationic amphiphilic drugs (CADs) are widely used in chronic pharmacotherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2. It has recently been shown that alpha-tocopherol (alpha-Toc) inhibits drug- and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3. The mechanisms of alpha-Toc action on drug kinetics and PL storage were studied in human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. 4. alpha-Toc did not influence the initial, pH-dependent rapid phase of drug uptake. It inhibited, in a dose-dependent manner, the slow and the cumulative phases of drug uptake and coincidently the accumulation of cellular PLs. 5. The inhibitory effects of alpha-Toc on CAD and PL accumulations depends on the ratio between CAD and alpha-Toc concentrations in the medium. This points to competition between alpha-Toc and CADs for PL complex formation. 6. Effectiveness of alpha-Toc on drug uptake varies among different CADs. It depends on its structural integrity but is independent of stereoisomerism. The inhibitory action is restricted to the piggyback slow drug uptake and therefore related to the proportion of membrane-mediated transport to permeation into lysosomes (rapid uptake). This proportion differs among CADs. 7. alpha-Toc prevents lysosomal membrane-PL storage, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that alpha-Toc restores membrane recycling, impaired by CAD exposure. 8. It remains to be tested in vivo whether alpha-Toc reduces CAD side effects without interfering with drug effectiveness.