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.     

The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression

Depression is related to the alterations of the central serotonergic system and some antidepressants achieve their therapeutic effects through alteration of serotonin (5-HT) (re)uptake. Peripheral biochemical markers, platelet and serum 5-HT concentrations, platelet monoamine oxidase (MAO) activity, plasma levels of cortisol and prolactin (PRL), were investigated in patients with major depression before and after 4 weeks of treatment with paroxetine (an inhibitor of 5-HT uptake) or tianeptine (a stimulator of 5-HT uptake). Study was open, single center and included female depressed patients, 21 treated with tianeptine (37.5 mg/day) and 15 treated with paroxetine (20 mg/day), and 11 drug-free healthy women (controls). Before treatment, depressed patients as a group had significantly higher serum 5-HT and cortisol concentrations than healthy controls. There were no differences in the other biochemical markers. Response to antidepressant treatment was estimated according to the 50% fall in the initial scores of Hamilton Depression Rating Scale (HAMD) after 4 weeks of treatment. Good therapeutic response was observed in 47% and 45% patients treated with paroxetine and tianeptine, respectively. Paroxetine treatment induced significant decrease in platelet 5-HT concentrations in both responders and nonresponders, while no alterations in platelet 5-HT values were found in tianeptine-treated patients. There was a subgroup of depressed patients in paroxetine-treated group with high pretreatment platelet 5-HT concentration and later poor therapeutic response to paroxetine treatment. Serum 5-HT values, platelet MAO activity or plasma cortisol or PRL levels were unchanged after both treatments. The results suggest that pretreatment platelet 5-HT levels, but not other peripheral biochemical markers, might predict therapeutic outcome at least in paroxetine-treated patients.     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. I. Enhanced response in depression and mania

The serum cortisol concentration following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, a precursor of serotonin (5-HT), was significantly greater in unmedicated depressed and manic patients than in normal controls. Increases in serum cortisol levels greater than 5 micrograms/dL were significantly more frequent in both unmedicated depressed and manic patients than in the normal controls. There was significant test-retest reliability. Baseline serum cortisol concentration correlated negatively with the cortisol response to 5-HTP in normal controls. These results suggest increased 5-HT receptor sensitivity may be present, possibly in the hypothalamus or pituitary, in some patients with affective disorders. These results are consistent with the hypothesis that decreased serotonergic activity, which would be expected to produce increased 5-HT receptor sensitivity, may be present in both depression and mania.     

Long-term sertraline treatment and peripheral biochemical markers in female depressed patients

Serotonergic system is implicated in the pathogenesis of depression. Peripheral biochemical markers, platelet serotonin (5-HT) and platelet monoamine oxidase (MAO) activity were determined spectrofluorimetrically at baseline and after 4 and 24 weeks of sertraline (a selective serotonin reuptake inhibitor (SSRI)) treatment in 15 female nonsuicidal, nonpsychotic patients with major depression and compared with 15 drug-free healthy women. The aim of the study was to determine the effects of 4 and 24 weeks of sertraline treatment on platelet 5-HT concentration and platelet MAO activity in depressed patients subdivided according to the treatment response into remitters, responders and nonresponders after 4 and 24 weeks of sertraline treatment based on the 70%, 50-69% and <49% reductions in baseline Montgomery-Asperg Depression Rating Scale (MADRS) scores, respectively. Platelet 5-HT concentration was significantly lower in all depressed patients at baseline than in healthy subjects. Among patients, platelet 5-HT concentration or platelet MAO activity did not differ before treatment. There was no significant correlation between MADRS scores and peripheral biochemical markers. The limitation of the study was in a small number of patients, but its advantage was in a long-term (24 weeks) follow-up of both patients and healthy controls. Our results show that long-term sertraline treatment induced remission and response in 87% patients, decreased platelet 5-HT concentration after 4 and 24 weeks of treatment and decreased platelet MAO activity after 24 weeks and suggest that pretreatment values of platelet 5-HT and platelet MAO might not predict therapeutic outcome to sertraline treatment in female depressed patients.     

Platelet serotonergic markers in posttraumatic stress disorder

The neurobiological basis of posttraumatic stress disorder (PTSD) is believed to involve alterations in different neurotransmitter systems, and recent studies elucidated the role of serotonin (5-hydroxytryptamine, 5-HT) in PTSD. The data on the role of 5-HT have been obtained using blood platelets as a peripheral model for central serotonergic neurons. The reports suggested that platelet 5-HT concentration and monoamine oxidase (MAO) activity might serve as biological, even trait, markers for particular mental disturbances. Since the data on the peripheral serotonergic markers in PTSD subjects are controversial, the aim of the study was to determine platelet 5-HT concentration and platelet MAO activity in war veterans with PTSD, war veterans who did not develop PTSD, and in war veterans who were prisoners of war and developed PTSD. Platelet 5-HT concentration and MAO activity did not differ significantly between war veterans with or without PTSD, and prisoners of war with PTSD. Clinician-Administered PTSD Scale (CAPS) scores did not differ between war veterans with PTSD and prisoners of war, but Montgomery-Asberg Depression Rating Scale (MADRS) scores were significantly higher in prisoners of war who developed PTSD than in war veterans with PTSD. There was no significant correlation between platelet 5-HT concentration or platelet MAO activity and CAPS or MADRS scores within these groups. Platelet 5-HT concentration was slightly higher and platelet MAO activity slightly lower in prisoners of war with PTSD, than in all other groups. These findings suggest that platelet 5-HT concentration and platelet MAO activity are not altered in three drug-free groups--war veterans who did or did not develop PTSD, or in prisoners of war with PTSD--and that these platelet serotonergic markers are not associated with symptoms of PTSD or comorbid depression.     

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.     

Platelet MAO activity and the cortisol response to dexamethasone in major depression

Previous studies have sometimes found a positive relationship between platelet monoamine oxidase (MAO) activity and dexamethasone nonsuppression in depressed patients. To assess this relationship in more detail, we examined the association between these two biological variables in unmedicated depressed patients. A positive correlation between platelet MAO activity and 8:00 AM serum cortisol levels following an overnight dexamethasone test (1 mg) was observed. The relationship between high and low platelet MAO activity (median split) and suppression of serum cortisol levels was also significant. These relationships were stronger in bipolar patients. Multiple regression revealed that postdexamethasone 8:00 AM dexamethasone levels and platelet MAO activity were independent predictors of the 8:00 AM cortisol levels following dexamethasone. The possibility that platelet MAO activity may be a peripheral marker of brain serotonergic activity which in turn may affect various aspects of the hypothalamo-pituitary-adrenal axis activity, is discussed. We also found that all nine depressed patients studied greater than or equal to 15 days after admission were suppressors. Platelet MAO activity, but not 8:00 AM pre- or postdexamethasone serum cortisol, was related to the severity of depression.     

Platelet monoamine oxidase activity in elderly depressed outpatients

Platelet monoamine oxidase (MAO) activity was assayed in 42 unmedicated, elderly, RDC depressed, unipolar outpatients over 60 years of age, 17 nondepressed controls, and 17 younger volunteers without psychiatric illness. Elderly depressed women (n = 22) had significantly higher MAO activity than sex- and age-comparable controls. No significant relationships between MAO activity and duration of current depressive episode, duration of illness, or family history of affective disorder were obtained. These results extend to elderly female outpatients the finding that depression is associated with increased platelet MAO activity, exceeding the normal age-related increase.     

Biological studies of DSM-III psychotic disorders. I. Platelet measures and apomorphine-induced growth hormone response

The relationship between DSM-III schizophrenia, major affective disorders, and the psychotic disorders not elsewhere classified (PDNEC) can be explored through studies which attempt to determine whether these disorders can be differentiated from one another and normal controls by biological measures. Preliminary results of an ongoing project which utilizes measures of blood platelet monoamine oxidase (MAO), serotonin (5-HT) uptake, and 5-HT content, and the apomorphine-induced increase in growth hormone (GH) to accomplish these goals are reported here. DSM-III major affective disorders (bipolar disorder and major depression) can be differentiated from normal controls by the V max of platelet 5-HT. Platelet 5-HT V max of bipolar disorder, depressed type, is significantly different from that of schizophrenia and PDNEC. Elevated platelet 5-HT content is present in black schizophrenic patients compared to black normal controls. Platelet MAO was increased in a small group of schizophreniform female patients. There was no difference in the apomorphine-induced GH response between any of the diagnostic groups. If confirmed in a larger series of patients, these results tend to identify the PDNEC more closely with schizophrenia than the major affective disorders.     

Role of norepinephrine in depression

This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and the therapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletion studies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved in antidepressant action, but the specific impairment that underlies depression is unclear and is likely to vary among patients. Results from neurotransmitter depletion studies in depressed patients who have responded to treatment suggest that, while interactions between NE and 5-HT are likely, neither of these 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressant drugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability of NE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent on the availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic and serotonergic systems-such as mirtazapine-may be dependent on the availability of both neurotransmitters for their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjects or worsened depression in unmedicated symptomatic patients with major depression. This finding suggests that the cause of depression is more complex than just an alteration in the levels of 5-HT and/or NE. For some patients, depression may be more directly caused by dysfunction in brain areas or neuronal systems modulated by monoamine systems. We propose that antidepressant drugs may enhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependent but as yet undiscovered process, restore function to brain areas modulated by monoamine neurons. Future research should focus on understanding the adaptive changes that follow enhancement of synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus. Research investigating the neurobiology of depression may be more informed if the focus is shifted to investigating areas of the brain modulated by monoamine systems rather than the monoamine systems themselves.     

Effects of amoxapine on serotonin uptake in human blood platelets of depressed patients and normal controls

The effect of amoxapine and imipramine on the serotonin (5-HT) uptake of blood platelets from depressed patients and normal controls was studied ex vivo or in vitro, respectively. Amoxapine was approximately one-tenth as potent as imipramine in inhibiting 5-HT uptake in blood platelets from normal controls in vitro. Both drugs inhibited 5-HT uptake in a competitive manner. However, ex vivo studies demonstrated that imipramine produced a mixed inhibition and amoxapine, a competitive inhibition of 5-HT uptake. There was no relationship between the change in the platelet affinity for 5-HT after treatment with amoxapine and clinical response to amoxapine.     

Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [I]-DOI

Abnormalities in the serotonergic system have been implicated in the pathophysiology of depressive disorders. Human platelets possess serotonin-2A (5-HT(2A)) receptors, and previous research using LSD or ketanserin as ligands have indicated that their number is increased in depressed patients. Compared to other ligands previously used in platelet studies, DOI is highly selective for the 5-HT(2A) receptor and binds to its high-affinity state, therefore labeling only the receptors that are biologically coupled to the G-protein. We determined the density (Bmax) and the affinity (Kd) of 5-HT(2A) receptors labeled by [(125)I]-DOI in platelets from 21 untreated patients with major depression and 21 healthy volunteers. The density of the 5-HT(2A) binding sites was found to be increased in platelets from female depressed patients as compared to controls. No changes were observed in the Kd. We did not find any relationship between the binding parameters and either the severity of the depressive episode or the suicidal tendencies of the patients. Our results show that the number of coupled platelet 5-HT(2A) receptors is increased in depressed patients, indicating that platelet 5-HT(2A) receptor function is enhanced in depression.     

Decreased platelet alpha-2 adrenoceptor density in major depression: effects of tricyclic antidepressants and fluoxetine.

BACKGROUND: It has been suggested that major depression is accompanied by a subsensitivity of central alpha 2-adrenoceptors (alpha 2-ARs) and, consequently, by an impaired negative feedback on the presynaptic catecholaminergic neuron, which, in turn, may induce a disinhibition of noradrenergic output and norepinephrine release in response to any activation. METHODS: The maximum number of platelet binding sites (Bmax) and their affinity for [3H]-rauwolscine, a selective alpha 2-AR antagonist, were measured in unmedicated and medicated major depressed patients and in normal volunteers. Specific binding was defined as that inhibited by idazoxan, another alpha 2-AR antagonist. RESULTS: Unmedicated major depressed patients had significantly decreased platelet [3H]-rauwolscine binding Bmax values compared to normal volunteers. [3H]-rauwolscine binding Kd values did not differ significantly between unmedicated major depressed patients and normal controls. [3H]-rauwolscine binding Kd values were significantly higher in depressed patients treated with tricyclic antidepressants than in unmedicated patients. Subchronic treatment with fluoxetine did not significantly alter either [3H]-rauwolscine binding Bmax or Kd values. [3H]-rauwolscine binding Bmax values were significantly greater in men than in women. CONCLUSIONS: The results suggest that i) major depression is accompanied by decreased platelet alpha 2-AR density; and that ii) subchronic treatment with tricyclic antidepressants, but not fluoxetine, results in a decreased affinity of rauwolscine for platelet alpha 2-ARs.     

Blood platelet monoamine oxidase activity, serotonin uptake and release rates in anorexia and bulimia patients and in healthy controls

Platelet monoamine oxidase (MAO) activity, serotonin uptake rate and serotonin efflux rate have all been suggested to be markers for central serotonergic mechanisms. Platelet MAO activity is associated with certain personality traits, with low activity linked to traits such as impulsiveness, sensation-seeking and avoidance of monotony, all possible expressions of low central serotonergic activity. Low platelet serotonin uptake rate has been connected to unipolar depression and the rate of efflux, in the presence of the ATP uncoupler CCP, higher in bipolar depressives than in controls. Platelet MAO was found to be lower in 16 consecutive female inpatients fulfilling the DSM-III criteria for bulimia nervosa than in 12 female controls. Rates of serotonin uptake and efflux in the presence of CCP were, on the other hand, similar to the controls. In the controls there were no correlations between platelet MAO activity and any of the other parameters estimated. Vmax for the platelet uptake of serotonin correlated positively with the Km for the uptake, but not with any other parameter. The uninfluenced rate of efflux of serotonin correlated positively with the efflux in the presence of the ATP uncoupler CCP.     

Alteration of platelet serotonergic mechanisms and monoamine oxidase activity in premenstrual syndrome

Platelet uptake and content of 5-hydroxytryptamine (5-HT), platelet monoamine oxidase (MAO) activity, and plasma free and total tryptophan levels were determined in patients diagnosed with premenstrual syndrome (PMS) and in control subjects. The Vmax of 5-HT uptake and 5-HT content in platelets of PMS patients were significantly decreased during the premenstrual phase (cycle days -9 to -1) compared to control subjects. Platelet MAO activity was significantly lower postmenstrually (cycle days 5-9) in PMS patients compared to the premenstrual phase. There were no differences in plasma free and total tryptophan levels between PMS patients and control subjects during either interval. As platelets are believed to be a peripheral model for central serotonergic neurons, the results suggest that PMS symptomatology may be related to alterations in serotonergic neuronal mechanisms.     

Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women

Serotonin (5-hydroxytryptamine, 5-HT) is involved in the regulation of hypothalamic-pituitary-adrenal axis (HPA) activity and prolactin (PRL) secretion. The present study examined the relationship between platelet 5-HT and plasma cortisol and PRL concentrations in 20 schizophrenic, 25 depressed, and 25 healthy women. At the time of blood sampling, the schizophrenic and depressed patients had been drug-free for at least 7 days. Platelet 5-HT, plasma cortisol and PRL concentrations were determined by spectrofluorimetric, radioimmunoassay and immunoradiometric methods, respectively. Platelet 5-HT concentration was significantly higher in schizophrenic patients than in depressed patients or in healthy controls, while it was significantly lower in depressed patients than in healthy controls or in schizophrenic patients. Plasma cortisol levels were significantly increased both in schizophrenic and in depressed patients compared with values in healthy controls. Values of plasma PRL were similar across groups. A significant correlation was found between platelet 5-HT and plasma cortisol, and platelet 5-HT and plasma PRL concentrations in healthy controls, but not in schizophrenic or depressed patients. There was no significant relationship between plasma PRL and cortisol levels in any of the groups. Our data, although obtained on peripheral biochemical markers, indicate that depression and schizophrenia are characterized by disturbed 5-HT transmission and dysregulated HPA axis activity.     

Platelet monoamine oxidase and sex hormones in a population of depressed patients

The association between changes in platelet MAO activity and Major Depressive Episode have been demonstrated. Cyclical changes in sex hormones serum levels had never been related with changes of MAO activity in depressed patients. Platelet MAO activity, oestrogen serum levels, progesterone serum levels and testosterone serum levels, have been measured in drug free depressed patients: 22 men and 42 women. This study demonstrates no relationship between serum levels hormons and platelet MAO activity, measured in men and in women. If young women are separated from menopaused women, platelet MAO activity is negatively correlated with oestrogen serum levels, in non menopaused women. Significance of this variation in studies about the use of MAO as a biochemical marker in depression is discussed.     

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression

One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.     

5-Hydroxytryptophan-induced cortisol response and CSF 5-HIAA in depressed patients

To determine if the enhanced cortisol response to oral administration of the serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) that has been reported in unmedicated depressed and manic patients might be related to brain monoaminergic metabolism, the authors assessed correlations between 5-HTP-induced cortisol response and CSF in nine depressed patients. They found a significant negative correlation with CSF levels of 5-hydroxyindoleacetic acid, a 5-HT metabolite, but not with CSF levels of other monoamine metabolites. This finding is consistent with the hypothesis that low presynaptic brain serotonergic activity may be related to enhanced cortisol response to 5-HTP in depressed patients.     

Measurement of platelet monoamine oxidase using three different substrates in patients with alcoholism and schizophrenia

The platelet monoamine oxidase (MAO) activities in alcoholism and schizophrenia were investigated by means of simultaneous determination, using beta-phenyl-ethylamine, tryptamine and serotonin as substrates. No significant difference was found between the MAO levels in the alcoholic and schizophrenic groups, when tryptamine was used as a substrate, but both groups showed lower values than the controls. On the other hand, beta-phenylethylamine, a specific substrate for MAO B used as a substrate, showed no significant difference between the alcoholic and control groups in the activities. These two groups showed higher values in MAO activity than the schizophrenic group, whereas when MAO activity was estimated using serotonin, platelet enzyme was found to be inhibited significantly in alcoholism, and the level of activities in the schizophrenics was similar to that of the controls. Moreover, the beta-phenylethylamine inhibition curve obtained serotonin as the substrate in the pooled platelets of 50 normal human subjects, and the MAO activity could not be inhibited by higher concentrations than the Km value of serotonin. These findings suggested that there might be two interacting catabolic sites having different substrate affinities in blood platelet MAO. Thus, it could be speculated that serotonergic catabolic sites of MAO in the platelets are disturbed in the alcoholics, while beta-phenylethylaminergic catabolic sites of platelet MAO are inherently vulnerable in schizophrenia.