Increased 3H-clonidine binding in the platelets of patients with depressive and schizophrenic disorders

To examine whether alpha 2-adrenergic receptor function is altered in affective and schizophrenic disorders, we determined 3H-clonidine binding in platelets obtained from 33 normal control subjects and from 24 patients with depressive, 22 patients with schizophrenic, 18 with bipolar, and 8 patients with schizoaffective disorders during a drug-free period. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) for high affinity 3H-clonidine binding was computed by Scatchard analysis. Comparison of the diagnostic groups indicated that the Bmax in depressed, schizophrenic, and schizoaffective patients was significantly higher than in normal controls, but there were no significant Bmax differences between bipolar patients and controls. Comparison of the Kd among the diagnostic groups indicated no significant differences among the groups or between patient diagnostic groups and normal controls. Baseline Bmax in schizophrenic patients was significantly correlated with the decrease in Brief Psychiatric Rating Scale (BPRS) scores after treatment, suggesting a relationship between baseline Bmax and clinical response. Treatment with lithium caused a significant decrease in the baseline Bmax, whereas treatment with desipramine or trifluoperazine did not cause significant changes in the baseline Bmax. Our results thus indicate an increase in the number of alpha 2-adrenergic receptors in depressed and schizophrenic patients as compared to normal controls.     

Serotonergic markers in platelets of patients with major depression: upregulation of 5-HT2 receptors.

The uptake of [3H]5-HT and the density (Bmax) as well as affinity (Kd) of 5-HT uptake sites labelled with [3H]paroxetine and of 5-HT2 receptors labelled by [3H]LSD were determined in platelets from 25 medication-free patients with major depression and 20 normal controls. The density (Bmax) of 5-HT2 receptors was found to be significantly increased (by 52%) in platelets from depressed patients, particularly females. No changes were found in the affinity (Kd) of 5-HT2 receptors and in 5-HT uptake or [3H]paroxetine binding parameters. Density of 5-HT2 receptors positively correlated with that of [3H]paroxetine sites in control but not in depressed subjects. No correlation was found between the HAMD scores and Bmax of [3H]LSD binding. The results suggest that upregulation of platelet 5-HT2 receptors is a useful biological marker in major depression, particularly in females.     

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.     

3H-imipramine binding to freshly prepared platelet membranes in depression

3H-Imipramine binding was measured in freshly prepared platelet membranes from 47 drug-free major depressives and 46 healthy controls. Where possible, platelet binding in depressed subjects was repeated following treatment. A significant negative correlation was found between Bmax and assay protein concentration and Bmax values were corrected for this effect. Adjusted Bmax was significantly lower (by 14%) in female depressed patients than in female control subjects, and the difference was of similar magnitude premenopausally and postmenopausally. No such difference was found in males. Kd did not differ significantly between depressed and control subjects. Multiple regression analysis confirmed significant effects on Bmax of presence of depressive illness, age (positive correlation), and season (higher in summer). Within the depressed sample, Bmax was significantly lower in those subjects with obsessional features. Endogenicity (Research Diagnostic Criteria or Newcastle), dexamethasone suppression test result, drug-free interval, family history of depression, depressive psychosis, suicidal ideation, and past history of suicide attempts were not significantly related to Bmax. Paired comparisons revealed no significant effect on Bmax of 6 weeks' treatment with imipramine, maprotiline, or BRL 14342 or of a course of electroconvulsive therapy.     

Further evidence supporting the role of the serotonin system in suicidal behavior: a preliminary study of suicide attempters

The 3H-imipramine binding parameters (Bmax and Kd) were studied in platelets from female suicide attempters and from healthy volunteers. The Bmax was significantly lower among suicide attempters, with no modification of the Kd. These results provide support of the hypothesis that decreased serotonin function may play a role in suicidal behavior.     

The prediction of suicidal intent in depressed patients

The aim of the present study was to examine the relationships between suicidal ideation or suicidal attempts and severity of depression, presence of personality disorders, and sociodemographic factors in a population of depressed in-patients. A total of 338 adult depressed psychiatric in-patients were examined and classified according to DSM-III criteria as having major depression with or without melancholic or psychotic features, adjustment disorder with depressed mood or dysthymic disorder. Scores on the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI) and Zung Self-Rating Depression and Anxiety Scales (SDS and SAS) were measured. We found that suicidal ideation was significantly related to severity of depression (according to the HDRS and all self-rating scales), a lower global assessment of functioning the year before hospitalization, and previous psychiatric hospitalizations. The items with the strongest predictive value for suicidal ideation were hopelessness, depressed mood, feelings of guilt, loss of interest and low self-esteem. These symptoms predicted 43% of the variance in suicidal ideation. None of the above predictors of suicidal ideation was related to suicidal attempts. Depressed patients with a personality disorder attempted significantly more suicidal attempts and showed more suicidal ideation than depressed patients without personality disorder. No significant correlations were found between suicidal ideation or suicide attempts and gender, marital status, employment status or psychosocial stressors during the previous 6 months.     

Effect of protein concentration on kinetic constants (Kd and Bmax) of 3H-imipramine binding in blood platelets

3H-imipramine binding was studied in the blood platelets of 80 normal controls and 50 depressed (psychotic and nonpsychotic) patients. Protein concentration in the incubation mixture, and Kd and Bmax values were correlated in normal controls and depressed patients. A small but significant correlation between protein in the incubation mixture and Bmax was observed in normal controls and depressed patients. There was also a significant correlation between protein and Kd of imipramine binding in the blood platelets of unipolar psychotic depressed patients. However, analysis of covariance to remove the effect of protein on Kd and Bmax did not change the basic finding of decreased Bmax in the blood platelets of psychotic depressed patients.     

Platelet alpha 2-adrenergic receptors in depressed patients and healthy volunteers: the effects of desipramine.

Binding parameters (Bmax and Kd) of alpha 2-adrenergic receptors were studied in platelets from 14 depressed patients and 18 control subjects. Using 3H-clonidine (a partial alpha 2-adrenergic agonist) as the ligand and membranes, prepared from platelets isolated under physiological conditions, we found no significant differences in Bmax and Kd between medication free patients and control subjects. Platelet binding parameters in the depressed patients did not correlate with plasma levels of norepinephrine, epinephrine or MHPG. Age had a significant positive effect on platelet alpha 2-adrenergic receptor Bmax in both groups, and may have masked the patient-control differences. Treatment with desipramine for 28 days had no effect on the binding parameters in depressed patients when compared to pretreatment values. Adding desipramine to platelets of control subjects 'in vitro' did also not affect binding parameters. Our findings suggest that receptor binding studies with a partial alpha 2-adrenergic agonist in platelet membranes are not a useful model to test the hypothesis of a central supersensitive adrenergic system in depression.     

Platelet serotonin-2 receptors in obsessive-compulsive disorder

To examine the role of serotonin-2 (5-HT₂) receptors in obsessive-compulsive disorder (OCD), we studied 5-HT₂ receptors in platelets obtained from patients with OCD (n = 20) during a drug free baseline period, as well as in normal control subjects (n = 25). The maximum number of binding sites (B_max) and the apparent dissociation constant (K_d) of 5-HT₂ receptors were determined by receptor binding techniques using ¹²⁵I-lysergic acid diethylamide (LSD) as radioligand. We observed that the mean B_max of ¹²⁵I-LSD binding in platelets of patients with OCD was not significantly different when compared with normal control subjects. There was also no significant difference in K_d values between patients with OCD and normal control subjects. To examine whether the baseline 5-HT₂ receptors are related to the severity of illness, we determined the relationships of the baseline B_max and K_d with baseline scores of the Hamilton Depression Rating Scale (HDRS), the Yale-Brown Obsessive-Copullsive Scale (Y-BOCS), and the National Institute of Mental Health (NIMH) Obsessive-Compulsive scale (GOCS). We found no significant correlation betwwen baseline B_max and K_d with the baseline HDRS, Y-BOCS, or NIMH-GOCS scores. Our results do not indicate abnormal 5-HT₂ receptors in platelets of patients with OCD.     

Relationship between seasonal patterns of platelet serotonin uptake and 3H-imipramine binding in depressed patients and normal controls

1. Significant seasonal variations were found in the velocity of serotonin (Vmax) uptake and the density of 3H-imipramine binding sites (Bmax) in blood platelets from normal controls. 2. Peak 3H-imipramine (3H-IMI) binding was found in February whereas peak serotonin (5HT) uptake was found in June and these measures were not correlated in paired comparisons. 3. Both Vmax and Bmax values of depressed patients deviated from the normal seasonal pattern with lower uptake and binding in the patient group. 4. A comparison of Vmax and Bmax deviations from the normal patterns of uptake and binding revealed a significant correlation between these measures such that patients with low Vmax values were the same as those with low Bmax values. 5. The results support previous claims that the 3H-IMI binding site may be closely associated with, or identical to, a 5HT transport carrier. 6. A significant correlation between uptake and binding further suggests that a common defect may be responsible for observed decreases in Vmax and Bmax values of depressed patients.     

Peripheral serotonergic markers in acutely suicidal patients. 1. Comparison of serotonergic platelet measures between suicidal individuals,nonsuicidal patients with major depression and healthy subjects

Summary Background. A robust association between “suicidality” and deficits of the serotoninergic neurotransmission has been claimed in the past. However, many studies having investigated the relationship between suicidality and peripheral indicators of serotoninergic neurotransmission suffer from considering only one or a very small number of potentially useful serotoninergic parameters, whereas a synoptic multidimensional approach appears to be more appropriate. Furthermore, the psychiatric context within which suicidal behaviour occurs should be considered when interpreting biochemical findings of patients with suicidal ideation and suicide attempts. Methods. In the present study 5 peripheral serotonergic markers, (platelet 5HT concentration, 5HT uptake activity, 5HT_2A receptor binding characteristics, MAO-B activity and tryptophan concentration in plasma) were assessed simultaneously. Of the 60 acutely suicidal inpatients (ICD-10: F43.xx, n = 52; F31/32/33, n = 8), 45 were suicide attempters. Data of 28 nonsuicidal patients with major depression (F31, n = 4; F32, n = 14; F33, n = 10) and 123 healthy volunteers represented the control groups. Results. Mean platelet 5HT concentration was significantly lower in suicidal inpatients when compared to nonsuicidal depressed patients, but did not differ from the figure in healthy subjects. Nonsuicidal depressed patients showed significantly higher mean platelet-5HT concentration than healthy controls. Mean V_max of 5HT uptake in washed platelets, but not in platelet-rich plasma, was significantly higher in suicidal patients than in healthy controls, not, however, when compared to nonsuicidal depressed patients. Mean K_D for the platelet 5HT_2A receptor and MAO-B activity were significantly lower in suicidal patients as compared to nonsuicidal depressed patients and healthy controls. The observed differences in peripheral serotonergic markers between groups are partially due to a significant gender effect. A lower MAO-B activity was observed only in suicidal females, while the higher V_max of 5HT uptake in washed platelets of suicidal patients was due to suicidal males. Conclusions. In view of conflicting observations made by other authors and the present findings on suicidal patients with adjustment disorder it remains doubtful whether and if so to which extent platelet studies can provide valid information on serotonergic mechanisms related to suicidal behaviour.     

Alpha 2-adrenergic receptors in platelet membranes of depressed patients: increased affinity for 3H-yohimbine

Specific binding to alpha 2-adrenergic receptors was studied in the platelets of 31 patients with major depressive disorder and 18 normal controls using the selective antagonist 3H-yohimbine. Receptor density for depressed patients (Bmax = 88 +/- SD 45.1 fmoles/mg) was not significantly lower than that for controls (124 +/- SD 78.1 fmoles/mg). The affinity of the receptor for yohimbine was significantly greater in depressed patients (Kd = 1.05 +/- SD 0.47 nM) than in controls (Kd = 1.47 +/- SD 0.63 nM). This is consistent with the hypothesis of increased alpha 2-adrenergic receptor sensitivity in depressive disorders. Past studies of alpha 2-adrenergic receptors on platelets are reviewed, and the importance of designing studies with sufficient statistical power is discussed.     

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.     

Effects of light therapy on suicidal ideation in patients with winter depression

BACKGROUND: Recent case reports suggest that some patients with seasonal affective disorder (SAD) may become suicidal after initial treatment with light therapy. This retrospective study sought to determine the effects of light therapy on suicidal ideation in patients with SAD. METHOD: The cases of 191 depressed patients with SAD by DSM-III-R or DSM-IV criteria treated with an open trial of morning light therapy using cool white fluorescent light boxes (2500 lux for 2 hours per day or 10,000 lux for 30 minutes per day) for 2 weeks were retrospectively analyzed. Patients had been rated before and after treatment with the expanded Hamilton Depression Rating Scale (SIGH-SAD). RESULTS: Sixty-seven percent of patients were rated as clinical responders to light therapy. There was significant improvement in the SIGH-SAD suicide item score, with 45% of patients showing a reduction in score. Only 6 patients (3%) had slight worsening of suicide scores. No patients attempted suicide or discontinued light therapy because of emergent suicidality. CONCLUSION: Light therapy relieves suicidal ideation in patients with SAD consistent with overall clinical improvement. Emergence of suicidal ideas or behaviors is very uncommon with light therapy.     

Pilot randomized clinical trial of an SSRI vs bupropion: effects on suicidal behavior, ideation, and mood in major depression

Randomized controlled trials in depressed patients selected for elevated suicidal risk are rare. The resultant lack of data leaves uncertainty about treatment in this population. This study compared a serotonin reuptake inhibitor with a noradrenergic/dopaminergic antidepressant in major depression with elevated suicidal risk factors. We conducted a double-blind, randomized, clinical pilot trial of paroxetine (N=36) or bupropion (N=38) in DSM IV major depression with a suicide attempt history or current suicidal ideation. The effects during acute (8 weeks) and continuation treatment (up to 16 weeks) were measured. Main outcomes were suicidal behavior and ideation. The secondary outcome was modified 17-item Hamilton Depression Rating Scale score subtracting the suicide item (mHDRS-17). Treatment was not associated with time to a suicidal event and no treatment main effect or treatment × time interaction on suicidal ideation or mHDRS-17 was found. Exploratory model selection showed modest advantages for paroxetine on: (1) mHDRS-17 (p=0.02); and (2) in a separate model adjusted for baseline depression, for suicidal ideation measured with the Beck Scale for Suicidal Ideation (p=0.03), with benefit increasing with baseline severity. Depressed patients with greater baseline suicidal ideation treated with paroxetine compared with bupropion appeared to experience greater acute improvement in suicidal ideation, after adjusting for global depression. Given the lack of evidence-based pharmacotherapy guidelines for suicidal, depressed patients-an important public health population-this preliminary finding merits further study.     

Treatment-emergent suicidal ideation during 4 months of acute management of unipolar major depression with SSRI pharmacotherapy or interpersonal psychotherapy in a randomized clinical trial

Background: To date, few randomized controlled trials (RCTs) of major depression have examined suicidal ideation as an outcome measure. Our aim is to determine the incidence of treatment‐emergent suicidal ideation (ESI) and behaviors during the acute phase of treatment with an SSRI antidepressant or interpersonal psychotherapy (IPT) in patients with unipolar major depression. Methods: In a two‐site RCT, 291 adult outpatients with nonpsychotic major depression and a Hamilton Depression Rating Scale (HDRS) score ≥15 were randomly allocated to IPT or SSRI. Participants who did not remit with monotherapy received augmentation with the other treatment. ESI was defined as a postbaseline HDRS suicidality item score ≥2 or a postbaseline Quick Inventory of Depressive Symptomatology (QIDS) score ≥2 in patients with a baseline score ≤1. Results: Of the 231 participants who had no suicidal ideation at baseline, 32 (13.8%) subsequently exhibited ESI on at least one postbaseline visit. Time to suicidal ideation was significantly longer in patients allocated to SSRI compared to those allocated to IPT (HR = 2.21, 95% CI 1.04–4.66, P = .038), even after controlling for treatment augmentation, benzodiazepine use, and comorbidity with anxiety disorders. Worsening of suicidal ideation occurred in 7/60 patients who had suicidal ideation at baseline. In the large majority of cases, suicidal ideation was successfully managed with the study protocol. Conclusions: In the context of careful monitoring and frequent contact, selective serotonin reuptake inhibitor (SSRI) was associated with a lower risk of ESI than IPT and both SSRI and IPT appeared to be safe treatments for patients with past suicide attempts, none of whom exhibited ESI during the study. Depression and Anxiety, 2011.© 2011 Wiley‐Liss, Inc.     

Lack of association between fluoxetine and suicidality in bulimia nervosa.

BACKGROUND: The coincidence of major depressive disorder in bulimia nervosa ranges from 35% to 80%. Because of this comorbidity and because suicidality (suicidal acts and ideation) is an inherent part of depression, assessment of the risk of suicide in patients with bulimia nervosa is of considerable interest. METHOD: Data from United States Investigational New Drug double-blind, placebo-controlled fluoxetine clinical trials in bulimia nervosa were analyzed comprehensively to assess the potential association between fluoxetine treatment and suicidality in 785 patients with DSM-III-R bulimia nervosa. Patients were predominantly women (98%), aged 17 to 63 years; of the randomly assigned patients, 16.9% exhibited 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of 17 or greater at baseline (range, 0-31). Incidence of suicidality was analyzed by the incidence difference method. RESULTS: No fatal suicidal acts occurred; 9 (1.15%) of 785 patients made nonfatal attempts; 24 (3.06%) experienced emergent (text-defined) suicidal ideation. No statistically significant increases in the incidence of suicidal acts or suicidal ideation were observed among fluoxetine-treated compared with placebo-treated patients. A smaller percentage of fluoxetine-treated (2.0%) than placebo-treated (3.8%) patients experienced emergence of substantial suicidal ideation (change in baseline HAM-D Item 3 [suicide item] score of 0 or 1 to 3 or 4 during therapy). A statistically significantly greater proportion of fluoxetine-treated than placebo-treated patients experienced improvement in suicidal ideation (decrease in HAM-D Item 3 score) from baseline to endpoint (p = .026). CONCLUSION: Analyses of the incidence of suicidal acts and suicidal ideation did not indicate an increased risk of suicidality in patients with bulimia nervosa treated with fluoxetine compared with those treated with placebo.     

Platelet 3H-clonidine and 3H-imipramine binding and plasma cortisol level in depression

Platelet 3H-clonidine (alpha 2-adrenergic agonist) binding and 3H-imipramine binding were measured and the Dexamethasone Suppression Test performed in 17 normal controls and 14 unmedicated depressed patients in order to clarify the relationship among these three biological markers. Increases in the Bmax and the Kd for 3H-clonidine binding and decreases in the Bmax for 3H-imipramine binding of the platelets from depressed patients were observed when compared with controls. There was a significant positive correlation among 3H-clonidine Bmax, the basal (predexamethasone) plasma cortisol levels, and the severity of depression, as indicated by the Hamilton Depression Rating Scale. On the other hand, no significant correlation was observed in 3H-imipramine binding between the Bmax and the severity of depression or between the Bmax and the basal plasma cortisol levels. There was no statistically significant correlation between the Bmax of 3H-clonidine binding and that of 3H-imipramine binding in depression, but there was a trend toward correlation in normal controls.     

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.