Electroconvulsive shock therapy and maximum binding of platelet tritiated imipramine binding in depression

We studied the tritiated imipramine binding values in platelets from 12 hospitalized untreated patients with endogenous depression and found a significant decrease in maximum binding (Bmax) values compared with a control population of the same age and sex. There were no changes in the equilibrium dissociation affinity constant values between the untreated depressives and the control population. After at least six sessions of electroconvulsive therapy and at the time when a significant clinical improvement of depression was confirmed, the Bmax value of tritiated imipramine binding in platelets was slightly increased but was still significantly below that of the control values. However, when six of these patients were reexamined after 12 to 18 months, at a time when they were euthymic, the Bmax of tritiated imipramine binding in platelets was found in the same range as the values of the control population. Our results indicate that clinical improvement precedes the changes in Bmax of tritiated imipramine binding in platelets from depressed patients. The tritiated imipramine binding in platelets is a useful biologic marker in affective disorders. Furthermore, our results suggest that tritiated imipramine binding in platelets may be a state-dependent biologic marker in depression.     

Platelet imipramine binding in endogenous depressed patients and controls: relationship to platelet MAO and 5HT uptake during successful imipramine treatment

Platelet imipramine binding was measured in 25 unmedicated depressed patients and 25 age- and sex-matched healthy controls. In the patients, the measurement was repeated after 3 weeks and 2 months of imipramine treatment leading to clinical recovery. No significant differences in imipramine binding were found between controls and unmedicated patients. In the latter, imipramine administration produced a progressive change in the binding characteristics, increasing the apparent Kd and decreasing the number of binding sites (Bmax). The results suggest that platelet imipramine binding is not altered in depression and that changes in this parameter are the consequence of the presence of imipramine in the blood stream. However, such changes accompany changes in other biological parameters, such as platelet monoamine oxidase and serotonin uptake, seen in the same patients throughout imipramine treatment, suggesting that the drug acts on a wide range of normal or altered serotonin-related cellular mechanisms while it accelerates the clinical recovery from depression.     

Biological markers in juvenile depression

3H-p-Aminoclonidine binding to platelets of children and adolescents with major depressive disorder was compared to that of a healthy control population. Significantly higher alpha 2-adrenoceptor Kd and Bmax values were observed in the patient population. 3H-Dihydroalprenolol binding to lymphocyte membranes of the same patient population showed significantly higher beta-adrenoceptor Bmax values than controls. Control females had significantly higher beta-adrenoceptor Kd values than control males, and the female patients had significantly lower beta-adrenoceptor Kd values than control females. 3H-Imipramine binding to platelets of these patients showed significantly higher imipramine Kd values in patients with a suicide attempt, whereas the imipramine Bmax values were significantly increased in patients with major depressive disorder with or without a suicide attempt. We propose that increased platelet alpha 2-adrenoceptor Kd and Bmax values, together with increased platelet imipramine Kd values, may serve as possible biological markers for children and adolescents with major depressive disorder and a tendency toward suicide. Elevated platelet imipramine and lymphocyte beta-adrenoceptor Bmax values may be biological markers for juvenile depression, and decreased beta-adrenoceptor Kd values may be a biological marker for depression in young females.     

Imipramine binding sites on platelets of patients with major depressive disorder

3H-Imipramine binding to platelets of patients with primary, unipolar major depressive disorder was investigated and compared to that of a normal, healthy control population. No significant differences could be demonstrated between either the Kd or the Bmax values of the two groups. A negative correlation was observed between imipramine Bmax values and the Hamilton anxiety ratings of the depressed patients. Patients who displayed psychomotor retardation tended to have lower platelet imipramine Bmax values than patients with psychomotor agitation. It is suggested that platelet imipramine Bmax values may be a biological marker for subtypes of depression.     

Lack of seasonal variation in platelet [3H]imipramine binding in humans

The Bmax of [3H]imipramine (IMI) binding has been reported to be reduced in platelets of depressed untreated patients as compared with normal controls. However, it has also been suggested that this difference could be related to the failure to take into account seasonal variations in the binding parameters for [3H]IMI recognition sites in platelets. For this reason, [3H]IMI binding was studied throughout 1 year in platelet membranes from 11 control volunteers, with blood samples collected once a month. The Bmax and Kd values of [3H]IMI binding showed no significant variation throughout the 12-month period of the study. These results indicate that in the control population, the platelet [3H]IMI binding parameters remain stable, and that the decrease in Bmax observed in depressed untreated patients reflects a genuine difference, which may be considered to be a biological marker in depression.     

Platelet [3H]imipramine binding in psychiatric disorders

The Bmax and Kd values for [3H]imipramine binding were measured in platelets from drug-free normal controls and schizophrenic and depressive patients. No differences among groups were found. Exacerbated and remitted patients with either schizophrenia or depression did not differ in platelet [3H]imipramine binding parameters. No correlations were observed between platelet [3H]imipramine binding parameters and measures of symptom severity among actively ill patients with either schizophrenia or depression.     

Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression

The number (Bmax) and affinity (Kd) of platelet-tritiated imipramine binding sites was determined in young and middle-aged controls 50 years of age and younger (n = 25), elderly normal controls over 60 years of age (n = 18), patients who fulfilled DSM-III criteria for major depression who were under 50 years of age (n = 29), patients who fulfilled DSM-III criteria for major depression who were 60 years of age and older (n = 19), and patients who fulfilled both DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease (n = 13). Both groups of depressed patients (under 50 and over 60 years of age) exhibited significant reductions (decreases 42%) in the number of platelet-tritiated imipramine binding sites with no change in affinity, when compared with their age-matched controls. There was little overlap in Bmax values between the elderly depressed patients and their controls. The patients with probable Alzheimer's disease showed no alteration in platelet-tritiated imipramine binding. There was no statistically significant relationship between postdexamethasone plasma cortisol concentrations and tritiated imipramine binding. These results indicate that platelet-tritiated imipramine binding may have potential utility as a diagnostic adjunct in geriatric depression, and moreover that the reduction in the number of platelet-tritiated imipramine binding sites is not due to hypercortisolemia.     

Platelet [3H]imipramine binding in patients with panic disorder

[3H]imipramine binding to platelets was measured in 17 drug-free panic disorder patients and 14 healthy controls. No difference in Bmax or Kd values was found between the two groups. Patients with a past history of major melancholic depression or severe agoraphobia had similar binding parameters as panic disorder patients without a history of depression or severe agoraphobia.     

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.     

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 [3H]imipramine binding in affective disorders: trait versus state characteristics

Platelet [3H]imipramine binding (Bmax) was determined in 67 patients with major affective illness (33 euthymic bipolar, 34 depressed unipolar) and 58 normal control subjects. Bipolar patients had significantly lower Bmax values than did control subjects. The mean Bmax in the unipolar patients was lower than in the control subjects, but the difference was not statistically significant. Dissociation constant (Kd) values did not distinguish patients in either category from control subjects. The significantly lower Bmax in euthymic bipolar patients and the apparent state independence of Bmax in some but not all unipolar patients suggest that platelet imipramine binding may be a trait marker in a subset of affective disorders.     

Changes in [3H]5-HT uptake and [3H]imipramine binding in platelets after chlorimipramine in healthy volunteers. Comparison with maprotiline and amineptine

In the platelets of normal healthy volunteers (n = 8) taking chlorimipramine (50 mg/day) for 1 week, the saturable uptake of [3H]5-hydroxytryptamine (5-HT) was fully inhibited at the end of the week, but returned to control values after 2 weeks washout. The Bmax of [3H]imipramine binding was decreased by 63% at the end of the treatment and remained significantly decreased below control values after 1 week washout, whereas the Kd values were increased at the end of the treatment, but had returned to baseline values after 1 week washout. The time course of recovery following the administration of chlorimipramine showed some variation between subjects, but it was necessary to wait up to 4 weeks of washout before the Bmax of [3H]imipramine returned to baseline levels. In contrast, neither 1-week treatment with maprotiline (50 mg/day) nor with amineptine (100 mg/day) changed the parameters of [3H]5-HT uptake or [3H]imipramine binding in platelets from healthy volunteers. These results support the following conclusions. (1) [3H]Imipramine binding in platelets can be down-regulated by relatively low, subtherapeutic doses of chlorimipramine. (2) It is possible to dissociate [3H]imipramine binding parameters from [3H]5-HT uptake because the time course of recovery was clearly different, indicating that [3H]imipramine labels a site linked with, but different from, the 5-HT recognition site in the transporter complex. (3) A washout of antidepressants of 4 weeks may be needed when studying the parameters of [3H]imipramine binding in platelets from depressed patients if the previous medication involved chlorimipramine. For antidepressants like maprotiline or amineptine, that act through mechanisms other than inhibition of 5-HT uptake, the time of washout appears to be less critical, although it is not possible to rule out the existence of some secondary modifications influencing the 5-HT transporter complex.     

Tritiated imipramine binding in obsessive-compulsive volunteers and psychiatrically normal controls

The authors evaluated platelet tritiated imipramine binding in 22 outpatients with obsessive-compulsive disorder (OCD) and 22 psychiatrically normal controls matched for age and gender. Mean maximal binding site density (Bmax) and equilibrium dissociation affinity (Kd) values were not significantly different. In OCD patients, Bmax was positively associated with age but was not associated with age of onset, gender, personality disorder, or five measures of illness severity. Eight patients with OCD were subsequently treated with clomipramine up to 300 mg/day for 10 weeks. Among these 8 patients, Bmax values had a 65% mean decrease from baseline, but Bmax values did not change among 7 OCD patients receiving placebo. The results suggest that a reduced density of tritiated imipramine binding sites may not be associated with OCD.     

Circadian variation in platelet imipramine binding during the day in healthy subjects

Platelet tritiated imipramine binding values in healthy controls vary considerably from study to study. A possible contributor to such variation might be a circadian rhythm affecting binding, although previous studies of this have been contradictory. Platelet imipramine binding was examined in 12 healthy, medication-free subjects studied at 8 a. m., 11 a. m., 4 p. m., and 10 p. m. during one day. Imipramine binding was determined on platelet membranes, using 0.8-8 nM 3H-imipramine, and nonspecific binding was defined by 50 microM desipramine. All samples from a given individual were assayed simultaneously. The intra-assay coefficient of variation was 6.3 percent. There was no evidence of significant differences in binding capacity or affinity (Bmax or Kd) at different times of day. Circadian variation was explored using COSINOR analysis (DeMet et al., 1989). There was no evidence of circadian variation in binding using this model, even when only the variable portion of binding was considered for each individual. Intraindividual variation in binding was substantial, with a mean coefficient of variation of 29 percent for Bmax and 38 percent for Kd. The possible basis of this variation is unclear, but may reflect the presence of "occult" binding sites in the membrane, or the effect of endogenous modulators of binding. The interrelationship of Bmax and Kd may also be a factor. It was considered that low-affinity binding did not account for a significant part of the variation in Kd in this assay. The utility of imipramine binding as a biological marker of depression may be limited by such levels of intraindividual variation in binding parameters.     

A longitudinal study of intact platelet 3H-imipramine binding in 12 normal human subjects

Most investigators have measured binding of 3H-imipramine to platelet membranes, but some of the preparations may have contained varying proportions of intracellular protein because of contamination with incompletely lysed platelets. Since binding to membranes has been expressed with reference to the amount of protein in the membrane preparation, it is not surprising that there are discrepancies and a wide range of reported values for platelet imipramine binding in the literature. We have now completed a 9-month study of the binding of 3H-imipramine to intact platelets obtained monthly from 12 normal subjects. Using the intact platelet assay, as described by Friedl and Propping, we found that both Bmax and Kd for 3H-imipramine binding exhibited large month-to-month variations and no consistent seasonal trend was observed. The substantial variation in both Bmax and Kd among normal subjects and among samples obtained from the same individual at different times may limit the clinical usefulness of these measurements. A single blood sample is unlikely to give reliable values for Bmax and Kd for comparison purposes.     

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.     

3H-imipramine binding in the frontal cortex of suicides

Imipramine binding (desipramine- and serotonin-sensitive) was determined in the frontal cortex of suicide victims and nonpsychiatric controls who died due to medical disease or accidents. There were no differences in Kd or Bmax of imipramine binding between controls and suicides. The Kd and Bmax values of serotonin-sensitive imipramine binding were significantly lower than desipramine-sensitive imipramine binding, both in controls and suicides. There were significant correlations between Kd and Bmax of serotonin-sensitive imipramine binding and desipramine-sensitive imipramine binding in suicides but not in controls.     

Effects of antidepressant treatments on platelet tritiated imipramine binding in major depressive disorder

The effects of four antidepressant treatments on platelet tritiated imipramine binding have been studied in 51 hospitalized patients with severe major depressive disorder. There was an increase in maximum binding (Bmax) during the first week of treatment with antidepressants and electroconvulsive therapy, which was further magnified after three weeks' treatment with the serotonin uptake blockers alaproclate and zimeldine hydrochloride, but the Bmax values returned to baseline levels with nortriptyline hydrochloride and electroconvulsive therapy. The equilibrium dissociation affinity constant (Kd) did not change with any of the treatments. On reexamination one or two years after admission to the study, Bmax had not reached control values in clinically recovered, drug-free patients. Low pretreatment Bmax was associated with delusions during illness and with a poor long-term clinical outcome. There was no correlation between binding parameters and monoamine metabolite concentrations in the cerebrospinal fluid, either before or during treatment.     

Unaltered platelet [3H]-imipramine binding in dementia of the Alzheimer type

High-affinity [3H]-imipramine binding to platelets was evaluated in 11 patients suffering from dementia of Alzheimer type (DAT) in comparison to 12 normal controls. The [3H]-imipramine binding values (Bmax and Kd) did not differ between the DAT patients and the controls. Previous studies have demonstrated hypofunction of central serotonergic system in this disease, including reduced imipramine binding to brain. Thus, it seems that the low imipramine binding in DAT is confined to the brain tissue and not reflected in the platelets.     

3H-imipramine binding in blood platelets of schizophrenic patients

3H-Imipramine binding was studied in the blood platelets of 51 unmedicated chronic schizophrenic patients. Univariate analyses of log-transformed data revealed that Bmax was significantly lower in schizophrenic patients than normal volunteers; Kd was nonsignificantly higher in the schizophrenics. A multivariate analysis of variance indicated the Kd and Bmax both differ significantly between normal controls and schizophrenic patients in the direction of increased Kd and decreased Bmax in the schizophrenics. These results indicate that decreased platelet imipramine binding is not specific for major depression.