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.     

Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Relationship to plasma cortisol levels before and after dexamethasone administration

We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (beta max) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the beta max values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between beta max and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n = 14) and at 11 PM after dexamethasone administration (n = 15). These data suggest that the reported decrease in beta max found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.     

Platelet imipramine binding and serotonin uptake in obsessive-compulsive patients

Platelet imipramine binding was measured in 16 drug-free nondepressed patients (aged 20-61 years, mean ± SD 35 ± 8) suffering from obsessive-compulsive disorder (OCD) and in 16 sex-, race- and age-matched healthy controls. Imipramine binding capacity and affinity were not different in the 2 groups. Platelet serotonin (5-HT) uptake capacity, V_max, was also measured in 15 of these patients and their matched controls. V_max was significantly higher in the patients (309 ± 149 pmol/10⁹ cells/min) than in the controls (181 ± 110). An increase in platelet 5-HT uptake supports the involvement of 5-HT in OCD and may suggest that a hyperactive serotonergic system is present in this disorder.     

Platelet imipramine binding in depressed children and adolescents.

Kinetic constants of platelet imipramine binding were determined in youths with major depression, and a contrast group. Subjects actively depressed (N = 10) had significantly fewer imipramine binding sites (Bmax) (877 +/- 148 fmol/mg protein) than recovering depressives (N = 12) (1220 +/- 428 fmol/mg protein) and contrasts (N = 10) (1270 +/- 230 fmol/mg protein). Affinity constants (Kd) (1.14 +/- 0.36 nM, 0.97 +/- 0.31 nM, and 1.17 +/- 0.39 nM, respectively) were similar among the groups. Actively depressed males but not females had fewer imipramine binding sites than both their sex-matched comparison groups. Although actively depressed females' Bmax was significantly lower than recovering depressed and nondepressed males, neither age, Tannner stage, nor circannual rhythms influenced Bmax, but suicidality may be associated with low Bmax. A decrease in Bmax may be a state-specific marker of major depression in boys or associated with a depressive disorder with a suicidal history.     

Platelet MAO activity and the dexamethasone suppression test in depressed patients

Platelet monoamine oxidase (MAO) activity and postdexamethasone cortisol levels were determined in 26 depressed patients. The incidence of cortisol nonsuppression and the mean postdexamethasone cortisol levels were significantly higher in patients with high MAO activity than in those with low MAO activity.     

Platelet and whole blood serotonin content in depressed inpatients: correlations with acute and life-time psychopathology.

Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +/- 27.3 versus 77.6 +/- 41.7 ng/10(8) platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +/- 41.5 ng/10(8) platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +/- 31.1 ng/10(8) platelets) and 27% greater than healthy controls (62.4 +/- 19.8 ng/10(8) platelets). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD). Nevertheless, BPD attempters had lower serotonin levels than BPD nonattempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r = 0.44, p = 0.04 and r = 0.41, p = 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.     

Platelet tritiated imipramine binding and MAO activity in Alzheimer's disease patients with agitation and delusions

Decreased platelet 3H-imipramine binding density and decreased monoamine oxidase (MAO) activity have been considered as biological characteristics of several neuropsychiatric disorders, and may be related to central serotonin defects. Since serotonin system defects occur in Alzheimer's disease (AD), and decreased brain 3H-imipramine binding density, and increased brain and platelet MAO activity are reported also, we studied platelet 3H-imipramine binding density (Bmax) and platelet MAO activity in AD outpatients without antecedent psychiatric disorder. AD subjects with significant symptomatic behavioral disorder, predominantly agitation and delusions, and AD subjects without symptomatic behaviors were compared with controls. Age, sex, mini-mental state examination score, and illness duration did not distinguish the two AD groups. The agitated/delusional group showed significantly lower Bmax values than uncomplicated AD subjects or controls. MAO activity was significantly increased among female AD subjects without symptomatic behaviors compared to those who were agitated or to controls. These results indicate that 3H-imipramine binding and MAO activity may distinguish AD subjects with agitation or delusions from those without symptomatic behaviors, and suggest the existence of a biologically based Alzheimer's behavioral subtype.     

Kinetic effects of desmethylimipramine treatment on platelet serotonin uptake in depressed patients: a comparison with imipramine

The kinetic effects of desmethylimipramine (DMI) on platelet serotonin (5HT) uptake were compared to those of imipramine (IMI) in eight DMI-treated depressed patients and seven IMI-treated depressed patients, and compared to values after patients were off drug for 19 (+/- 8 SD) and 33 (+/- 15) days. As expected, IMI was a stronger inhibitor of 5HT uptake than DMI during treatment, with the mean apparent Km in treated patients being elevated nearly threefold over that of the drug-free condition. In DMI-treated patients, the mean Km was elevated nearly twofold over that of the drug-free condition. Although DMI is considered a preferential norepinephrine uptake inhibitor, the results suggest the following: (1) Significant decreases in the apparent platelet 5HT affinity are achieved with DMI; (2) the inhibition kinetics in depressed patients are competitive; (3) there was a significant relationship between Km change and depression outcome with DMI discontinuation; and (4) DMI, as a metabolite, appears to contribute to the 5HT uptake inhibition of IMI in vivo.     

Platelet MAO activity, TRH test, and dexamethasone suppression test in depressed patients

Platelet MAO activity, TRH test and DST results were compared in 23 normal subjects and 13 depressed patients. Patients as a group were older in age, had higher levels of FT4-index and T3-uptake, and lower levels of MAO activity. There was no association between thyroid hormones, including TSH response, and MAO activity. Five patients were DST positive. They showed a higher average age and a higher T3-uptake value than DST negative patients. Serum T4 and MAO activity levels were normal in both groups. These data suggest that MAO activity and TSH are independently regulated in both normal subjects and depressed patients. They also suggest a reduced binding capacity for thyroid hormones in patients with positive DST.     

Platelet MAO and amitriptyline treatment

Some tricyclic antidepressants have been reported to inhibit monoamine oxidase (MAO) activity in vitro in addition to blocking the reuptake of norepinephrine and/or serotonin. While the inhibition of MAO is reversible, platelet MAO activity in depressed patients responding to amitriptyline treatment has been reported to be reduced after drug treatment. In a reverse design, we measured platelet MAO activity and drug levels in patients chronically being treated with amitriptyline and again 2 and 4 weeks after stopping the medication. Although tricyclic drug concentrations were initially within the therapeutic range and undetectable on placebo treatment, platelet MAO activities were unchanged.     

MAO inhibition and clinical response in depressed patients treated with phenelzine

The authors studied clinical response in 47 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Improvement on ratings for depression at Week 2 of treatment was correlated with percent MAO inhibition at Week 2 (r = .35, p less than .03), and the modest positive correlation that was found remained after the authors adjusted for the effects of baseline scores on the Hamilton Rating Scale for Depression, dose (mg/kg), and psychosis (partial correlation = .49, p less than .002). Further, the 23 patients ultimately classified as responders had a significantly greater percent MAO inhibition at Week 2 than did the 24 nonresponders (t = 3.02, p less than .005). Thus, the rate of MAO inhibition at Week 2 was significantly correlated with clinical improvement at Week 2 and final response status. These findings could not be explained by other potentially moderating variables such as sex, age, endogenicity, recurrence, and incapacitation.     

Double-blind comparison of amoxapine and imipramine in the treatment of depressed patients

A 5-week double-blind study compared amoxapine to imipramine (2:1 dosage ratio) in the treatment of depressed outpatients. The two agents were similar in anti-depressant efficacy and rapidity of action. The most common adverse reactions to both drugs were anticholinergic effects and sedation; cardiovascular effects were minimal. A few amoxapine-treated patients developed adverse effects typical of neuroleptic drugs: some experienced extrapyramidal signs, one developed galactorrhea, and most showed elevated plasma prolactin concentrations. Amoxapine was associated with significant neuroleptic activity in plasma. No correlation was found between blood levels of either drug and therapeutic response.     

Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls

Platelet monoamine oxidase (MAO) activity and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were simultaneously measured in 20 currently depressed patients, 11 recovered depressed patients, 15 nondepressed suicide attempters, and 42 healthy control subjects. Both 5HIAA and HVA were positively and significantly correlated to platelet MAO activity in the healthy subjects, but not in any of the patient groups. Suicide attempters had significantly lower CSF 5HIAA than nonsuicidal patients.     

Platelet MAO activity and age at onset of depression in elderly depressed women

Platelet monoamine oxidase (MAO) activity was assayed in 38 elderly depressed women and 16 matched controls. The depressed women whose illness began at age 55 or earlier (N = 19) had significantly lower MAO activity than patients with later onset (N = 19) or controls.     

Platelet serotonin reuptake inhibition and response to SSRIs in depressed adolescents

OBJECTIVE: The authors examined platelet serotonin reuptake inhibition and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed adolescents. METHOD: Twenty-three depressed adolescents participating in pharmacokinetic studies of SSRIs had platelet serotonin reuptake measured before and after 14-28 days of treatment. The Clinical Global Impression (CGI) improvement rating was determined on the basis of all clinical information and was performed blind to the platelet data. RESULTS: Improvement in depressive symptoms as rated with the CGI improvement subscale was significantly associated with the percentage change in platelet serotonin reuptake inhibition from pre- to posttreatment. Improvement in depression was also associated with absolute decrease in platelet serotonin reuptake when adjusted for the magnitude of baseline reuptake. CONCLUSIONS: Platelet serotonin reuptake inhibition may be an appropriate surrogate biological marker for the pharmacodynamic activity of SSRIs in depressed adolescents.     

Platelet MAO inhibition, urinary MHPG, and leukocyte beta-adrenergic receptors in depressed patients treated with phenelzine

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.     

Platelet MAO activity during treatment with pegylated interferon-alfa in melanoma patients

Depression and cognitive disturbance are well-known neuropsychiatric side effects of therapy with interferon-alfa (IFN-alfa). Aggression and irritability are also reported as side effects. Probably, central nervous system (CNS) serotonergic dysfunction is one of the underlying pathophysiological mechanisms of IFN-alfa-induced neuropsychiatric toxicity. Platelet activity of monoamine oxidase-B (MAO; EC1.4.3.4) is a possible indicator of central serotonergic function. Moreover, low platelet MAO activity is linked to impulsiveness, addiction and personality disorder. In this exploratory study in 17 high-risk melanoma patients, platelet counts, whole blood MAO, and platelet MAO activity were measured before and during therapy with IFN-alfa. Patients were randomized to treatment either with pegylated IFN-alfa (PEG-IFN-alfa) once a week at a dose of 6 microg/kg/week subcuteanously (s.c.) during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. for a total of 5 years, or to observation only. Blood samples were taken at baseline, 4 and 8 weeks and 3 months. During treatment with IFN-alfa, platelet counts decreased at 4 and 8 weeks and 3 months, while platelet MAO activity increased, both compared to baseline and compared to non-treated controls. Compared to non-treated controls, platelet MAO activity increased with 86.4% (95 CI: 52.9-127.2). No significant changes in platelet MAO activity were observed in the control group. This indicates that platelet MAO activity is influenced by IFN-alfa. Since platelet MAO activity is a model for CNS MAO-B activity, it may be speculated that CNS MAO-B activity will also be increased. This could influence serotonin (5-HT) metabolism and thereby contribute to the development of psychiatric disturbance. However, a preferential inhibition of platelet production cannot be ruled out. Hypothetically, the antiproliferative effects of IFN-alfa could interfere more strongly with the synthesis of platelets than with the synthesis of mitochondria. In that case, increased platelet MAO activity reflects an increased number of mitochondria per platelet.     

Changes in urinary catecholamines and their metabolites in depressed patients treated with amitriptyline or imipramine

The effects of treatment with amitriptyline (AMI) or imipramine (IMI) on changes in catecholamines and their metabolites in urine were studied in 95 unipolar and bipolar depressed patients. For the entire group, not separated by drug, substantial reduction in concentrations of all metabolites, but not catecholamines, occurred. Although catecholamine and metabolite change was similar for most substances assayed, there were some specific drug and diagnostic group differences. Vanillylmandelic acid (VMA) reduction was limited to bipolar patients; metanephrine (M) reduction to unipolar patients. Greater M and 3-methoxy-4-hydroxyphenylglycol (MHPG) reduction were associated with response in unipolar, but not bipolar patients. In bipolar, but not unipolar patients, norepinephrine (NE) rose in responders in contrast to reductions among nonresponding bipolar patients. The results suggest that effectiveness of blockade of reuptake of norepinephrine may be relatively more important for recovery in bipolar than in unipolar patients. Study of a battery of amine substances may contribute more information to our understanding of antidepressant drug effects on aminergic systems than analyses of MHPG alone.     

Increased serotonin platelet uptake after tianeptine administration in depressed patients

Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydroxytryptamine [5-HT]) uptake in rat brain. The effect of tianeptine on 5-HT platelet uptake was studied in 10 depressed patients treated for 28 days. Tianeptine increases Vmax of 5-HT platelet uptake during treatment without inducing any change in Km. As early as 2 hr after the first administration, Vmax increased significantly (+23%, alpha = 0.01). Although of a lesser magnitude, 5-HT platelet uptake remains increased after chronic administration (+14% on day 10 and +13% on day 28). This suggests that tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tricyclic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.     

Platelet serotonin concentrations in medicated schizophrenic patients.

1. The present study was conducted to investigate the effects of neuroleptic administration on platelet serotonin (5-HT) levels, and the relationships between platelet 5-HT levels, extrapyramidal symptoms (EPS) and psychopathology in schizophrenia. 2. The subjects were 49 regularly medicated inpatients who were diagnosed according to the DSM-IV criteria for schizophrenia. Each patient gave informed consent for the research involved in this study. All patients were first considered as one group and then divided into two groups: those with lower levels (LL) and those with higher levels (HL), according to their platelet 5-HT levels. Psychotic symptoms and EPS were assessed using the Brief Psychiatric Rating Scale and the Drug Induced Extra-Pyramidal Symptoms Scale, respectively. 3. (1) The mean level of the platelet 5-HT in the schizophrenics with neuroleptic-treatment was significantly lower than that in the normal subjects. (2) The mean level of the blood monoamine oxidase (MAO) in the schizophrenics tended to be lower than that in the normal subjects. (3) There was no significant difference in the mean scores of the positive symptoms, negative symptoms, or EPS between the LL and HL groups. (4) Platelet 5-HT levels were not correlated with blood MAO concentrations. 4. Overall, these results seem to indicate that (i) administration of neuroleptics lowers platelet 5-HT levels, and (ii) platelet 5-HT levels in the schizophrenics with neuroleptic-treatment do not reflect psychopathology of schizophrenia or severity of neuroleptic-induced EPS.