Efficacy of 1,000 mg effervescent acetylsalicylic acid and sumatriptan in treating associated migraine symptoms

Recently a new effervescent acetylsalicylic acid (ASA) tablet with high buffering capacity has been developed. In this double-blind, 3-arm, multicenter, parallel-group study, 433 patients were treated either with 1,000 mg effervescent ASA or 50 mg encapsulated sumatriptan or placebo. The primary endpoint was the percentage of patients with complete remission of the 3 accompanying symptoms nausea, photophobia and phonophobia within 2 h after intake of the study drug. 43.8% of patients treated with ASA, 43.7% of patients treated with sumatriptan and 30.9% of patients treated with placebo showed complete remission of all 3 accompanying symptoms (p < 0.05 for ASA and sumatriptan vs. placebo). Both active treatments were superior to placebo regarding the individual symptoms photophobia and phonophobia, but not for nausea. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (secondary objective) was 49.3% for ASA, 48.8% for sumatriptan and 32.9% for placebo. All active treatments were superior to placebo (p < 0.05). 25.3, 24.4 and 14.5% of patients treated with ASA, sumatriptan or placebo were pain free at 2 h. Drug-related adverse events were reported in 3.9, 4.7 and 6.7% of patients treated with placebo, ASA or sumatriptan. The study showed that administration of effervescent ASA leads to remission of the migraine symptoms nausea, photophobia and phonophobia, reduces migraine headache and is comparable to sumatriptan.     

L-carnitine replacement therapy in chronic valproate treatment

Ten epileptic children with chronic valproic acid (VPA) treatment were given L-carnitine for 14 days. As compared to age and sex matched control subjects the carnitine status of the VPA treated children showed carnitine insufficiency prior to the carnitine administration with lower total and free carnitine in plasma and in urine. In response to the extra intake the plasma free and esterified carnitines increased 1.7-fold. The daily excreted amount of esterified carnitines increased 6.5-fold (1.55 +/- 0.23 vs 10.1 +/- 1.68 mumol/kg/day, means +/- SEM, p less than 0.005) showing that a considerable part of the administered carnitine participated in the elimination of acyl groups from the body. The depressed level of beta-hydroxybutyrate in the plasma (31.8 +/- 7.42 vs controls 118.0 +/- 16.0 mumol/l, means +/- SEM, p less than 0.005) remained unaffected by the carnitine administration (29.7 +/- 7.06 mumol/l) suggesting that the hypoketonemia is not a direct consequence of the carnitine insufficiency. No differences were observed in the plasma level of free fatty acids, triglycerides and in insulin: glucagon ratios between the VPA treated and control subjects, suggesting that lipolysis of fats and the hepatic hormonal control mediated by these hormones are not the sites at which VPA causes reduced fasting ketogenesis. The plasma level of VPA and the seizure control remained unaffected by carnitine treatment.     

Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine

The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.     

A double-blind comparison study of nomifensine and imipramine in treating depressed patients

Nomifensine was compared to imipramine in treatment of 40 patients with endogenous major depressive disorder. After one week washout, patients were randomly assigned to 5 weeks treatment with Nomifensine or Imipramine. Mean scores for HAM-D, HAM-A, GAS were significantly improved in both treatment groups (P less than 0.01). Two agents were similar in antidepressant efficacy and rapidity of action. Nomifensine treatment group had fewer side effect, whereas the Imipramine group had more adverse experiences. Effects of Nomifensine on the ECG were compared to those of imipramine. Both drugs increased heart rate. Nomifensine less than imipramine. QT measurement interval revealed a statistically significant decrease in imipramine group. Plasma Nomifensine and imipramine concentrations were not correlated with clinical response, side effects or electrocardiographic parameters. The steady-state plasma concentration 105 +/- 47ng/ml for nomifensine, 860 +/- 773ng/ml for imipramine were offaimed respectively at the fixed dose (225mg/day) during the 35 treatment day.     

Carbamazepine/valproic acid interaction in man and rhesus monkey

Sodium valproate (VPA) was administered for 1 week (1 g b.i.d.) to seven epileptic patients receiving chronic carbamazepine (CBZ) therapy. Steady-state CBZ levels determined before and after VPA therapy were reduced by 3-59% in six patients and were unchanged in one patient. The plasma concentration ratio of carbamazepine-10,11-epoxide ( CBZE ) to CBZ increased in all patients by 11-500%. The plasma binding of CBZ was determined in six healthy volunteers given a single 400 mg CBZ dose with and without the coadministration of 1 g VPA in a cross-over design. The mean CBZ free-fraction was increased in three of the subjects (p = 0.008-0.031), decreased in one subject (p less than 0.002), and remained unchanged in two subjects when VPA was administered. Four male rhesus monkeys were infused intravenously with CBZ (15 mg h-1) for 5 days and then three consecutive 24-h infusions were given: I, CBZ alone; II, CBZ with 75 mg h-1 VPA; III, CBZ with 150 mg h-1 VPA. The mean free-fraction of CBZ and CBZE increased during infusions II and III from 31.5 +/- 2.7% to 33.6 +/- 2.6% (p less than 0.05) and 37.7 +/- 1.3% (p less than 0.01) for CBZ and from 46.9 +/- 9.2% to 53.6 +/- 5.7% (p greater than 0.05) and 60.1 +/- 4.0% (p less than 0.01) for CBZE . The clearance of free CBZ declined from 7.96 +/- 1.75 to 4.84 +/- 1.26 (p less than 0.01) and 4.12 +/- 1.75 (p less than 0.01) 1 kg-1h-1 during infusions II and III, respectively. The mean free CBZE /CBZ ratio increased from 0.12 +/- 0.03 to 0.24 +/- 0.03 and 0.36 +/- 0.04 during infusions II and III, respectively (p less than 0.001). These findings indicate a decrease in the elimination clearance of CBZE possibly coupled with a decrease in its formation clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences between sodium-dependent and desipramine-defined [3H]imipramine binding in intact human platelets

Measurements of sodium-dependent [3H]imipramine binding to intact human platelets from 20 human volunteers were made and compared to desipramine-defined binding, a method commonly employed in population studies of platelet [3H]imipramine sites. The density (Bmax) of sodium-dependent [3H]imipramine sides in platelets was significantly lower (449 +/- 36 sites/platelet) and the affinity (Kd) significantly higher (1.15 +/- 0.12 nM) than those obtained when excess desipramine was used to define specific binding (Bmax 654 +/- 33 sites/platelet, p less than 0.001; Kd 1.52 +/- 0.11 nM, p less than 0.001). There was no significant correlation between the density (Bmax) of sodium-dependent and desipramine-defined binding in individual subjects, suggesting that a different proportion of sites are labeled under the two assay conditions. No age-dependent variation was found in either Kd or Bmax values of sodium-dependent or desipramine-defined [3H]imipramine binding. The results suggest determination of sodium-dependent [3H]imipramine binding to intact platelets may be a useful measure for the estimation of [3H]imipramine recognition sites relevant to the serotonin uptake in studies of patients with affective disorders.     

Effects of Imipramine on Behavior and Brain Norepinephrine Metabolism in Tetrabenazine Treated Rats: Comparative Study of a Single Administration with Repeated Administrations of Imipramine

Abstract: The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO₄) level in the brain was measured. 1) A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO₄. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO₄. 2) The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO₄ in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of α-methyl-para-tyrosine (α-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. 3) The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO.J increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. 4) Several considerations were given to the above-mentioned results.     

Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury

Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of fampridine (fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using fampridine-SR in patients with chronic SCI are currently underway.     

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder

OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.     

Human plasma inhibitors of platelet serotonin uptake and imipramine receptor binding: extraction and heterogeneity

Human plasma contains a considerable concentration of low molecular weight substances that inhibit, in a dose-dependent manner, both high-affinity imipramine receptor binding and serotonin uptake in platelets. Incubation of plasma with alumina was used to extract and to partly characterize these imipramine-like inhibitors. The human plasma extract inhibited imipramine binding and serotonin uptake with median inhibitory concentration (IC50) of 0.18 +/- 0.1 and 0.36 +/- 0.15 mg/ml, respectively. Imipramine-like activity of the extract was markedly degraded by carboxypeptidase B and leucine aminopeptidase, but was resistant to neurominidase and phospholipases A2, C, and D. The elution profile of the extract after gel chromatography on Bio-Gel P-2 showed two major peaks of serotonin uptake and imipramine binding inhibition and three additional peaks of serotonin uptake inhibitory activity that did not have a significant effect on imipramine binding. The possible mechanism of pharmacological action of the imipramine-like inhibitors and their relation to development of affective illnesses remain to be clarified.     

Correlation between progressive adsorption of plasminogen to blood clots and their sensitivity to lysis

The binding of plasminogen to preformed human plasma clots immersed in citrated human plasma was measured and correlated with the sensitivity of these clots to lysis with recombinant tissue-type plasminogen activator (rt-PA), recombinant single-chain urokinase-type plasminogen activator (rscu-PA) or two chain urokinase-type plasminogen activator (tcu-PA, urokinase). When 0.15 ml plasma clots were compressed mechanically to about 1% of their original weight, and immersed in 0.15 ml plasma, 131I-labeled native plasminogen (Glu-plasminogen) adsorbed progressively from the plasma milieu onto the clot; binding was 3 +/- 1% (n = 10) after 1 h, 7 +/- 1% after 12 h and 12 +/- 1% after 48 h. This was associated with an increased sensitivity of the clot to lysis; 50% clot lysis in 4 h was obtained with 65 +/- 5 ng/ml (n = 3) rt-PA before and 30 +/- 5 ng/ml (n = 3) after 48 h preincubation in plasma (p less than 0.01), with corresponding values of 660 +/- 55 ng/ml (n = 3) and 280 +/- 25 ng/ml (n = 3) for rscu-PA, (p less than 0.01), and 800 +/- 85 ng/ml (n = 3) and 270 +/- 35 ng/ml (n = 3) for urokinase (p less than 0.01). Additional binding of plasminogen and increased sensitivity to lysis were reduced or abolished when the clot was preincubated in plasminogen-depleted or in t-PA-depleted plasma, or when 20 mM 6-aminohexanoic acid or 2,000 KIU/ml aprotinin were added.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated imipramine enhances sensitivity of the brain dopaminergic system related to exploratory behavior

Summary The influence of imipramine treatment on apomorphine-induced behavior was studied. Imipramine was administered twice a day for 14 days at 10 mg/kg. The control group received a single dose of imipramine. Both groups were tested at 48 hours after imipramine administration, using open field; the number of line crossings and episodes of rearing and looking into holes were counted as part of the exploratory behavior. Repeated, but not single, administration of imipramine increased the exploratory activity induced by apomorphine injection an effect which was blocked by haloperidol pretreatment. The results indicate that repeated imipramine administration enhances the sensitivity of brain dopamine receptors related to exploratory behavior.     

Interactions between imipramine and morphine on motility in rats: possible relation to antidepressant effects?

The aim of the present study was to evaluate whether morphine and the more modern antidepressant drug imipramine have common effects on behavior after both acute and chronic administration, and, in particular, to establish whether they act synergistically. In rats, morphine (15 mg/kg i.p.) produced a pronounced hypokinesia, followed by locomotor activation and stereotyped behavior. After repeated administration (eight times), tolerance to the hypokinesia developed, whereas locomotor activation and stereotypies occurred earlier and were more pronounced. Subacute pretreatment with imipramine (twice daily 10 mg/kg i.p. for eight days) enhanced and prolonged hypokinesia and delayed the manifestation of stereotypies and locomotor activation. In contrast, chronic treatment with imipramine (for 29 days) no longer inhibited morphine-induced stereotypies and locomotor activation, but seemed to enhance them when they were tested in rats repeatedly treated with morphine. When the same rats were tested with morphine (15 mg/kg) seven days after withdrawal of morphine and imipramine, morphine produced increased stereotypies and a slight enhancement of locomotion. The experimental conditions used excluded the possibility that conditioning phenomena might explain the enhancement of (probably dopamine-mediated) behavior. Furthermore, the results demonstrated that 1) acute administration of morphine and subacute administration of imipramine may act in a synergistic way, and 2) repeated administration of morphine and chronic treatment with imipramine also act synergistically, although contrary to the acute actions of both drugs. These interactions might be of therapeutic or toxicological relevance.     

Elevated plasma concentrations of alpha 1-acid glycoprotein, a putative endogenous inhibitor of the tritiated imipramine binding site, in depressed patients

The plasma concentration of alpha 1-acid glycoprotein, a putative endogenous inhibitor of the site labeled by tritiated imipramine, was measured by a radial immunodiffusion assay in 36 normal human volunteers and 51 drug-free patients who fulfilled DSM-III criteria for major depression. The depressed patients exhibited a significant elevation in the plasma concentration (+/- SEM) of alpha 1-acid glycoprotein (79.6 +/- 4 mg/dL) when compared with the age- and sex-matched controls (61.7 +/- 3 mg/dL). Fourteen of the 51 patients with major depression had plasma alpha 1-acid glycoprotein concentrations that were higher than the highest values of the normal controls. There was no relationship between plasma alpha 1-acid glycoprotein concentrations and sex or affinity of platelet tritiated imipramine binding of either the normal volunteers or the depressed patients. In the depressed patients, there was a significant positive correlation between plasma concentrations of alpha 1-acid glycoprotein and postdexamethasone plasma cortisol concentrations, and two measures of depression severity, the Montgomery-Asberg Rating Scale for Depression and the Center for Epidemiologic Studies-Depression Scale, and a significant negative correlation with age. These data provide the first evidence of alterations of an endogenous inhibitor of the tritiated imipramine binding site/serotonin transporter in depressed patients.     

Thyrotropin releasing hormone potentiates the effects of imipramine on brain serotonergic system

Daily administration of thyrotropin-releasing hormone (TRH) (20 mg/kg) for 10 days in 2 equally divided doses increased 5-hydroxytryptamine and/or 5-hydroxyindoleacetic acid levels in certain brain areas. Chronic imipramine treatment (10 mg/kg) for 10 days significantly decreased the levels of brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. When TRH was administered concurrently with imipramine (10 mg/kg), this neuropeptide significantly potentiated the effects of imipramine on lowering of endogenous levels of 5-hydroxytryptamine (striatum, hypothalamus) and 5-hydroxyindoleacetic acid (striatum, midbrain, pons-medulla). Our data provide a possible neurochemical basis for the reported potentiation of tricyclic antidepressant action by TRH.     

The Comparative Peripheral Anticholinergic-Like Adverse Event Profiles of Olanzapine and Risperidone

OBJECTIVE: To test the hypothesis that reported in vitro muscarinic receptor affinity differences between olanzapine and risperidone would be reflected in peripheral solicited anticholinergic adverse event frequencies. METHOD: Data from a double-blind, randomized trial of olanzapine versus risperidone in 339 patients (age range, 18-65 years) with DSM-IV schizophrenia spectrum acute psychosis were retrospectively analyzed. Subgroups based on the median of the mean daily drug dose were constructed (olanzapine 17 mg; risperidone 6 mg). Mean daily dose of adjunctive anticholinergic medication was compared using ANOVA, and frequencies of treatment-emergent solicited adverse events defined by the Association de Méthodologie et de Documentation en Psychiatrie (AMDP-5) were analyzed using categorical methods. RESULTS: Mean daily anticholinergic dose was significantly higher overall for the risperidone group (0.68 +/- 1.27 mg) than for the olanzapine group (0.27 +/- 0.76 mg) (p =.002). When only patients who did not receive anticholinergic adjunct therapy were considered, no significant differences in the frequency of specific anticholinergic adverse events occurred in olanzapine-treated patients as compared with risperidone-treated patients (p >/=.245). There was also no significant difference between olanzapine and risperidone in the frequency of any anticholinergic adverse event (p =.458). CONCLUSION: At clinically effective doses, olanzapine and risperidone did not differ significantly in frequency of peripheral anticholinergic events. These results support the view that, for olanzapine and risperidone, in vitro anticholinergic receptor binding (K(i) values) may not predict in vivo peripheral events.     

Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages

The often quoted investigation by Behnsen [4] provides some evidence for an increased permeability of the neonatal mouse blood-brain barrier (BBB) to trypan blue compared to the adult. Trypan blue, which circulates in plasma mainly bound to albumin, is commonly used as a macromolecular tracer, although Behnsen probably injected dyes in amounts exceeding the dye-binding capacity of plasma proteins. The Cerebrovascular permeability in neonatal and adult mice and rats was investigated using the visual tracers trypan blue and Evans blue and immunocytochemical staining for endogenous plasma proteins. By administering different concentrations of the dyes, the permeability of the BBB was assessed. The presence of the dyes in plasma as either dye-protein complexes or as free dye was measured by a plasma protein binding assay. When dyes occurred in plasma as macromolecular dye-protein complexes, dyes and plasma proteins were restricted to CNS regions normally devoid of a BBB in both neonates and adults. When unbound (free) dyes occurred in plasma, dyes were observed intraneuronally in regions without projections beyond the BBB in both neonates and adults corresponding to that observed by Behnsen; intraneuronal accumulation of plasma proteins also occurred in regions with projections confined to the BBB but only in neonates. It is concluded that the BBB to macromolecular tracers is fully developed at birth in mouse and rats. However, when free dye is present in plasma, there is a differential permeability to plasma proteins between neonates and adults.     

Diazepam autoinjector intramuscular delivery system versus diazepam rectal gel: A pharmacokinetic comparison

Rectal administration of diazepam (DZ) has been used effectively in patients with epilepsy who experience acute repetitive seizures, but rectal gel may be difficult to administer during a seizure and is subject to variable drug absorption. An intramuscular (IM) autoinjector DZ formulation may offer a practical alternative to rectal DZ. This single-center, open-label, 3-treatment, 3-period crossover study compared the pharmacokinetic and safety profiles of 10mg DZ administered rectally in 24 healthy, fasted and fed subjects versus IM autoinjector delivery in fasted subjects. Blood samples were collected at baseline and for up to 24h postdose and plasma DZ concentrations were determined by liquid chromatography and tandem mass spectrometry. There were no significant differences between plasma concentrations for rectal administration of DZ in fasted and fed subjects at any time point. Intramuscular DZ administration resulted in more rapid and less variable drug absorption than rectal delivery. At 30min postdose and at all subsequent evaluations, IM administration resulted in significantly higher areas under the curve versus rectal administration in fasted subjects (p<0.05). This significant difference was sustained throughout the remainder of the 24-h study period (p<0.05). All reported adverse events were considered mild, and none required treatment.     

Changes in platelet 3H-imipramine binding with chronic imipramine treatment are not state-dependent

One month of imipramine treatment increased both the Kd and Bmax of platelet 3H-imipramine binding in 11 endogenous unipolar depressed patients. Continued treatment (13 weeks) of 5 patients subsequently lowered the Bmax values of 2 patients who had initially shown the largest increases, so that binding was no longer significantly elevated after 13 weeks. The observed changes in Kd but not in Bmax, could be explained by the carryover of tightly bound drug to the binding assay, although neither of the measures were correlated with plasma imipramine levels. Posttreatment Bmax (4 weeks) values were inversely related to plasma cortisol levels, although a weak but positive correlation was found before treatment. No significant change was found in plasma cortisol with treatment. Clinical responses were not related to cortisol or Bmax changes, although optimal improvement was associated with extreme values (high and low) of pretreatment Bmax. The present results, obtained with imipramine, and similar results obtained after nortriptyline and electroconvulsive shock by others, suggest that at least some antidepressants may induce transient changes in the Bmax of platelet binding that are independent of affective state.     

Platelet tritiated imipramine binding in psychiatric patients: relationship to symptoms and severity of depression

The clinical and research significance of reduced imipramine binding has remained unclear despite considerable investigation. This study used an assay of demonstrated reliability to investigate the clinical correlates of imipramine binding to platelets in 63 depressed and 33 nondepressed psychiatric patients and 40 healthy control subjects. Both patient groups had Bmax values significantly lower than those of the healthy controls. Unequivocal associations between binding parameters and individual symptoms or groups of symptoms were not established, but a negative correlation between Kd and the number of adverse life events experienced in the preceding 6 months was apparent. These findings provide no support for the view that reduced binding is a trait marker for susceptibility to depression and cast doubt on its specificity as a state marker for the syndrome of depression.