Increased platelet intracellular calcium concentration in patients with bipolar affective disorders

Using the fluorescent indicator Fura 2, we measured the free intracellular calcium ion concentration in blood platelets of patients with untreated mania, bipolar depression, and unipolar depression; patients who had recovered from bipolar depression or mania; and age- and sex-matched controls. The baseline intracellular calcium ion concentration was significantly increased in platelets from patients with mania compared with controls. The free intracellular calcium ion concentration after stimulation with platelet-activating factor and thrombin was significantly higher in platelets of manic and bipolar depressed patients than in all other groups. The degree to which intracellular calcium ion concentration increased over baseline after stimulation was significantly lower in unipolar than in bipolar patients. These findings suggest that platelets of manic and depressed bipolar patients have a similar enhancement of intracellular calcium ion activity that is distinctly different from the decreased ability of platelets of unipolar patients to mobilize intracellular calcium in response to stimulation.     

Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients.

The authors measured intracellular Ca2+ concentrations in four manic and five bipolar depressed patients and seven comparison subjects. Platelet and lymphocyte intracellular Ca2+ concentrations were comparable. The patients' mean intracellular Ca2+ concentrations were higher than those of the comparison subjects and demonstrated more interindividual variation. These findings suggest a diffuse abnormality in mechanisms affecting intracellular calcium homeostasis in bipolar disorder.     

Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay.

BACKGROUND: A number of investigators have reported finding elevated basal and stimulated intracellular calcium levels in the platelets or lymphocytes of bipolar disorder patients. METHODS: Intracellular calcium was measured by a micro fura-2 fluorometric method in the platelets and lymphocytes of 30 affective disorder patients and 14 control subjects. RESULTS: We observed significantly elevated basal calcium concentrations in bipolar patient platelets and lymphocytes compared to control subjects. Bipolar patient platelet calcium responses to thrombin, serotonin, and thapsigargin were also significantly greater than control subjects. The peak calcium levels of lymphocytes of bipolar patients were greater than control subjects only when stimulated by thapsigargin. There were significant differences between bipolar and unipolar patients in basal and thapsigargin-stimulated calcium measures but not between bipolar I and bipolar II patients. Unmedicated versus medicated calcium measures were not significantly different. We also found little correlation between calcium measures and the severity of mood rating. CONCLUSIONS: Using this method, we were able to confirm and extend the work of others, indicating altered intracellular calcium homeostasis in the blood cells of bipolar disorder patients. In addition, our data suggest that storage operated calcium channels may be the source of the elevated intracellular calcium in platelets and lymphocytes of bipolar patients.     

Elevated platelet intracellular calcium concentration in bipolar depression

Baseline and thrombin-stimulated free intracellular calcium concentrations in blood platelets were significantly higher in untreated depressed bipolar patients than in untreated unipolar depressed patients or controls. Platelet intracellular calcium ion concentrations in euthymic-treated bipolar patients were equivalent to control values, suggesting but not proving a state-dependent change in intracellular calcium ion dynamics in bipolar depression. Unipolar and some subsets of bipolar patients appear not to exhibit this change.     

5-Hydroxytryptamine uptake by blood platelets of unipolar and bipolar depressed patients

The active transport of 5-hydroxytryptamine (5HT) by blood platelets of unipolar and bipolar depressed patients was determined. The 5HT uptake by platelets of bipolar patients was determined in depressive, euthymic and manic states. The 5HT uptake was always followed by studying platelets of healthy individuals of the same sex and age. The results confirm the known fact that there is a decreased 5HT active transport in platelets of unipolar depressed patients. On the other hand, the amount of 5HT transported by platelets of bipolar depressed patients was higher than that observed in platelets of healthy individuals. In manic and euthymic bipolar patients the uptake was similar to their matched controls.     

Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites.

The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.     

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.     

Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients

BACKGROUND: recent investigations have suggested that the phosphoinositide (PI) signal transduction system may be involved in the pathophysiology of bipolar affective disorders. Earlier studies in our laboratory have implicated altered PKC-mediated phosphorylation in bipolar affective disorder and in the clinical action of lithium. In the present study, we compared PKC activity and its translocation in platelets from subjects with bipolar affective disorder and three other groups. METHODS: subjects included 44 with bipolar disorder (acute manic episode), 25 with acute major depression, 23 with schizophrenia in acute exacerbation and 43 controls free of personal or family history of an Axis I disorder. Blood platelet membrane and cytosol PKC activity was measured before and after in vitro stimulation with serotonin (5-HT), thrombin and the direct PKC activator, PMA. In addition, we examined 5-HT-, thrombin- and PMA-elicited translocations of PKC isozymes from cytosol to the membrane in platelets of control subjects. RESULTS: in the basal state, manic subjects demonstrated higher membrane PKC activity than depressive and control subjects. The ratio of membrane to cytosol PKC activity was significantly higher in manic (1.10), as compared to control (0.84), depressed (0.93) or schizophrenic (0.93) subjects. Stimulation of platelets with 5-HT in vitro, resulted in greater membrane to cytosol ratio in the manic subjects compared to the three other groups. The responsiveness of platelets to PMA and thrombin was greater for manic subjects than for depressed and schizophrenic subjects, but not greater than the controls. In this measure both the schizophrenic and depressive groups were less active than controls. The results also demonstrate that platelets contain alpha-, beta-, delta- and zeta-PKC isozymes. While alpha- and beta-PKC isoforms were translocated from cytosol to membrane in response to serotonin, PMA and thrombin, serotonin also elicited the redistribution of delta-PKC and thrombin also activated zeta-PKC. CONCLUSION: the results demonstrate that a heightened PKC-mediated signal transduction is associated with acute mania and suggest a decreased transduction in patients with unipolar depression or schizophrenia.     

11C-glucose metabolism in manic and depressed patients

The authors used positron emission tomography (PET) and 11C-labeled glucose to study 15 unmedicated patients with affective disorders and 7 control subjects. Diagnoses of affective disorders were based on DSM-III criteria, and symptomatology was evaluated by the Hamilton Rating Scale for Depression. Blood counts of 11C in both unipolar and bipolar patients did not differ from those in controls after oral administration of 11C-glucose. By contrast, brain counts of 11C in unipolar depressed patients were significantly lower, whereas those in bipolar manic patients were significantly higher, than in normal controls.     

Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.     

Psychomotor performance and monoamine function in bipolar and unipolar affective disorders.

BACKGROUND: Affective disorders are associated with prominent psychomotor abnormalities that may be related to changes in arousal or motivation due to altered catecholamine function. METHODS: We investigated relationships between performance on psychomotor tests of motor speed (reaction time and tapping speed) and visual tracking (trail making and dot placement) and catecholamine system function including cerebrospinal fluid (CSF) or urinary concentrations of catecholamines or their metabolites. Subjects were medicine-free inpatients with unipolar depression or with manic, depressive, or mixed episodes of bipolar disorder, and healthy controls matched by gender and stratified by age. RESULTS: Unipolar and bipolar depressed patients were impaired in motor speed, dexterity, and visual tracking, whereas manic and mixed patients did not differ from controls. Tapping speed correlated positively with CSF 3-methoxy-4-hydroxyphenylglycol in healthy controls and with CSF homovanillic acid in bipolar depressed subjects. Increased catecholamine function correlated with slowing in all other measures for patients with bipolar disorder. Relationships between catecholamines and psychomotor function were weaker in unipolar depressed subjects. Psychomotor function was related to severity of depression in bipolar, but not in unipolar, patients. CONCLUSIONS: These data suggest that catecholamine systems are associated with increased arousal and psychomotor impairment in patients with bipolar disorder. Similar behavioral changes have different neurotransmitter relationships in unipolar disorder.     

Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder

The authors investigated the effect of long-term lithium administration on intracellular calcium mobilization. The subjects were 13 women with bipolar affective disorder stabilized on lithium and 12 matched healthy controls. Total and ionized serum calcium, intracellular calcium ion concentration, plasma parathyroid hormone (PTH) and tyrotropin (TSH), serum electrolytes and cyclic AMP (cAMP) activity in platelets were measured. The serum electrolytes sodium, potassium and creatinine and plasma PTH and TSH were all within normal ranges in patients and controls and no differences were found between the two groups. No difference was found in basal and prostaglandin E1 (PGE1)-stimulated cAMP generation in platelets between patients and controls. However, total serum calcium and ionized serum calcium levels were higher in patients than in controls and there was a significant correlation between these two measures. In the patient group, serum lithium concentration correlated positively with stimulated levels of intracellular calcium in platelets. In the present study, no distinct hyperparathyroidism was found in lithium-treated patients. However, our findings indicate that lithium administration affects calcium metabolism in patients with bipolar affective disorder inducing mild hypercalcemia and a dose-dependent normalized calcium mobilization. Furthermore, our results did not support the hypothesis that lithium's primary site of action in bipolar illness may be on signal transduction mechanisms.     

Enhanced calcium response to serotonin in platelets from patients with affective disorders.

In this report we have investigated the intracellular calcium (Ca2+) mobilization mediated by serotonin 5-HT2A receptors in the platelets of 13 patients with bipolar disorder and 12 patients with major depression in comparison with 15 healthy control subjects. We found an enhanced intracellular Ca2+ rise in response to 5-HT in platelets from both bipolar patients and patients with major depression. The 5-HT2A receptor-mediated intracellular Ca2+ signaling mechanism may have an important role in the pathophysiology of affective disorders.     

The preliminary study of monoamine oxidase activity in platelets in patients with schizophrenia and affective disorder]

This paper has studied the MAO activity in platelets of 52 schizophrenic patients and 44 affective disorder patients. The results indicate that the MAO activity in platelets of schizophrenic patients is lower than that of normal group, especially the chronic schizophrenic patients. It's no difference between the acute schizophrenic patients and normal group. The MAO activity in platelets of bipolar affective disorder patients is much lower than that of normal group. Platelet MAO activity in male bipolar affective disorder is lower than that of female's, that of bipolar-manic effective disorder is lower than that of bipolar-depressive effective disorder. The MAO activity in platelets of unipolar depression is even lower than that of normal group.     

Dysfunctional attitudes and cognitive schemas in bipolar manic and unipolar depressed outpatients: implications for cognitively based psychotherapeutics

Dysfunctional thought patterns are presumed to underlie cognitive biases in mood disorder patients. However, few studies have compared dysfunctional thought patterns in bipolar manic and unipolar depressed patients. Cognitive schemas and dysfunctional attitudes were evaluated using the cognitive checklist for mania and Dysfunctional Attitudes Scale (DAS) in 34 bipolar manic, 35 unipolar depressed, and 29 nonpsychiatric control subjects. Unipolar depressed subjects had significantly higher total DAS scores and subfactor scores as compared with nonpsychiatric controls, whereas bipolar patients had intermediate scores between both groups. Significant correlations emerged between cognitive checklist for mania total and subcomponent scores and the DAS (total, performance subfactor, and approval subfactor scales) for the bipolar, but not the unipolar or nonpsychiatric control groups. Core beliefs among bipolar patients appear negativistic during manic phases, potentially reflecting an overcompensation for depression. The findings support clinical approaches targeting depressive cognitions regardless of the presence of manic symptoms.     

31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients

Most research with ³¹P-magnetic resonance spectroscopy (³¹P-MRS) in affective disorders has been done in the field of bipolar disturbances. Reduced frontal and temporal lobe phosphomonoester (PME) concentrations were measured in the euthymic state, whereas increased values were found in the depressed state. In bipolar-II patients reduced phosphocreatine (PCr) concentrations were reported in the euthymic, depressed, and manic state. The aim of the present study was to explore whether PME and PCr were also altered in the frontal lobe of major depressed, unipolar patients. Therefore, we used ³¹P-MRS to investigate the relative phospholipid and high-energy phosphate concentrations in the frontal lobe of 14 unipolar patients, mostly medicated, and 8 age-matched controls. We found increased PME and decreased ATP values. Other ³¹P-MRS parameters were not different in both groups. Phosphomonoester percentages correlated negatively with the degree of depression. Thus, the main alterations found in bipolar depressed patients could also be demonstrated in unipolar depressed patients. The results are discussed with regard to disturbed phospholipid and intracellular high-energy phosphate metabolism in depressed patients. Received: 2 December 1997 / Accepted: 14 July 1998     

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.     

Monoamine Oxidase Activity in Blood Platelets From Manic and Depressed Patients

To evaluate the possible abnormality in MAO activity in affective disorders, blood platelet samples were obtained from 80 patients with mania and depression. Blood-platelet MAO activity was measured by a newly developed assay procedures using serotonin as substrate. MAO activities in 121 normal adult subjects were in a range of 2.49-12.05 nM/mg protein/hour, with the mean values of 4.91 ±1.72 (±S.D.) for men and 6.88±1.99 for women. (p<0.001) MAO activities in the manic and depressed patients were in a range of 0.65–13.40 nM/mg protein/hour, and both manic and depressed patients showed the mean value very similar to that in the normal subjects. Bipolar depressed patients did not exhibited lower MAO activity in the blood platelets than other clinical subtypes of depressive illness, including unipolar, involutional, neurotic and chronic characterological, and first-episode depressions. No significant differences were established between these five subcategories of depression, while significant higher values were evident in female than male patients (p<0.001). No correlation was found between the MAO activity and serotonin levels in the blood platelets either in the normal subjects or in the depressed patients.     

Protein kinase A and Rap1 levels in platelets of untreated patients with major depression

We have recently reported altered levels of protein kinase A and Rap1 in patients with bipolar disorder. The purpose of the current investigation was to assess the levels of these proteins in platelets from untreated euthymic and depressed patients with major unipolar depression. Platelets were collected from 45 drug-free unipolar patients (13 euthymic and 32 depressed) and 45 healthy subjects. The levels of protein kinase A and Rap1 were assessed by Western blot analysis, immunostaining and computer-assisted imaging. The immunolabeling of the regulatory subunit type II of protein kinase A and that of Rap1 was significantly lower in untreated depressed patients compared with untreated euthymic patients and healthy subjects. No significant differences were found in the immunolabeling of both the regulatory type I and the catalytic subunits of protein kinase A among groups. Levels of the regulatory subunit type II of protein kinase A and Rap1 are altered in platelets of unipolar depressive patients. These findings may provide new insight about the relationship between components of cAMP signaling and affective disorders.     

Creatine monohydrate in resistant depression: a preliminary study

OBJECTIVES: Creatine plays a pivotal role in brain energy homeostasis, and altered cerebral energy metabolism may be involved in the pathophysiology of depression. Oral creatine supplementation may modify brain high-energy phosphate metabolism in depressed subjects. METHODS: Eight unipolar and two bipolar patients with treatment-resistant depression were treated for four weeks with 3-5 g/day of creatine monohydrate in an open add-on design. Outcome measures were the Hamilton Depression Rating Scale, Hamilton Anxiety Scale, and Clinical Global Impression scores, recorded at baseline and at weeks 1, 2, 3 and 4. RESULTS: One patient improved considerably after one week and withdrew. Both bipolar patients developed hypomania/mania. For the remaining seven patients, all scale scores significantly improved. Adverse reactions were mild and transitory. CONCLUSIONS: This small, preliminary, open study of creatine monohydrate suggests a beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of a manic switch in bipolar depression.