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.     

Calcium function in affective disorders and healthy controls

Calcium metabolism has been reported to be disturbed in some forms of affective disorder. We studied concurrently a battery of calcium measures in 29 unipolar, 14 bipolar depressed, 11 manic, and 10 healthy control subjects. In addition to measures of extracellular calcium, we studied intracellular calcium concentration in platelets and measures that reflect cellular capability to maintain a low intracellular Ca++ concentration in red blood cells (RBCs) and platelets. Plasma calcium was lower in unipolar and manic patients than in control subjects. Platelet calcium concentration was lower in unipolar than bipolar depressed patients. RBC Ca++ adenosine triphosphatase (ATPase) was lower in unipolar and control subjects than in bipolar depressed and manic patients. Platelet Ca++ ATPase and Ca++ uptake were inversely correlated with severity of illness in unipolar patients. In bipolar depressed patients, RBC Ca++ ATPase and platelet Ca++ uptake were inversely correlated with severity. In addition to indicating abnormalities in calcium activity in affective disorders, the data suggest that unipolar and bipolar patients differ in several measures and may have different pathophysiological disturbances in calcium metabolism.     

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.     

Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18

Cerebral metabolic rates for glucose were examined in patients with unipolar depression (N = 11), bipolar depression (N = 5), mania (N = 5), bipolar mixed states (N = 3), and in normal controls (N = 9) using positron emission tomography and fluorodeoxyglucose F 18. All subjects were studied supine under ambient room conditions with eyes open. Bipolar depressed and mixed patients had supratentorial whole brain glucose metabolic rates that were significantly lower than those of the other comparison groups. The whole brain metabolic rates for patients with bipolar depression increased going from depression or a mixed state to a euthymic or manic state. Patients with unipolar depression showed a significantly lower ratio of the metabolic rate of the caudate nucleus, divided by that of the hemisphere as a whole, when compared with normal controls and patients with bipolar depression.     

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.     

Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life

Objectives: Significant questions remain regarding both the incidence patterns of mood episodes in adolescents and young adults from the community and the conversion rate from unipolar to bipolar disorders. We addressed these issues by examining data from a prospective longitudinal community study to (i) determine the cumulative incidence of mood episodes and disorders in the first three decades of life; (ii) determine the risk for first onset of depression among individuals with a previous history of hypomanic/manic episodes and vice versa; and (iii) determine the clinical and treatment characteristics of these subjects. Methods: Using the Munich‐Composite International Diagnostic Interview, clinically trained interviewers assessed mood episodes and mental disorders in 3,021 community subjects (aged 14–24 at baseline and 21–34 at third follow‐up). Results: The estimated cumulative incidence at age 33 was 2.9% for manic, 4.0% for hypomanic, 29.4% for major depressive, and 19.0% for minor depressive episodes; overall, 26.0% had unipolar major depression, 4.0% bipolar depression, 1.5% unipolar mania, and 3.6% unipolar hypomania (no major depression). Overall, 0.6% and 1.8% had unipolar mania or hypomania, respectively, without indication for even minor depression. A total of 3.6% of the initial unipolar major depression cases subsequently developed (hypo)mania, with particularly high rates in adolescent onset depression (< 17 years: 9%). A total of 49.6% of the initial unipolar mania cases subsequently developed major depression and 75.6% major or minor depression. While bipolar cases had more adverse clinical and course depression characteristics and higher treatment rates than unipolar depressed cases, bipolar cases did not significantly differ in mania characteristics from unipolar mania cases. Conclusions: Unipolar and bipolar mood disorders are more frequent than previously thought in adolescence and young adulthood, a time period when both the recognition and the intervention rates by the healthcare system are rather low. ‘Conversion’ to bipolar disorder is limited in initial unipolar depression, but common in initial unipolar mania. The remaining unipolar mania cases appear to be significant in terms of clinical and course characteristics and thus require more research attention to replicate these findings.     

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.     

Insight into illness in patients with mania,mixed mania,bipolar depression and major depression with psychotic features

Dell'Osso L, Pini S, Cassano GB, Mastrocinque C, Seckinger RA, Saettoni M, Papasogli A, Yale SA, Amador XF. Insight into illness in patients with mania, mixed mania, bipolar depression and major depression with psychotic features. Bipolar Disord 2002: 4: 315–322. © Blackwell Munksgaard 2002 Background: Poor insight into illness is a common feature of bipolar disorder and one that is associated with poor clinical outcome. Empirical studies of illness awareness in this population are relatively scarce with the majority of studies being published over the previous decade. The study reported here sought to replicate previous report findings that bipolar patients frequently show high levels of poor insight into having an illness. We also wanted to examine whether group differences in insight exist among bipolar manic, mixed and unipolar depressed patients with psychotic features. Methods: A cohort of 147 inpatients with DSM‐III‐R bipolar disorder and 30 with unipolar depression with psychotic features, were evaluated in the week prior to discharge using the Structured Clinical Interview for DSM‐III‐R‐Patient Edition (SCID‐P), the Brief Psychiatric Rating Scale (BPRS) and the Scale to assess Unawareness of Mental Disorder (SUMD). Results: Insight into specific aspects of the illness was related to the polarity of mood episode: patients with mania showed significantly poorer insight compared with those with mixed mania, bipolar depression and unipolar depression. A linear regression analysis using SUMD score as the dependent variable and symptoms of mania as the independent variable found that specific manic symptoms did not account for level of insight. Similar results were obtained when the mean insight scores of patients with and without grandiosity were contrasted. Conclusions: We hypothesize that the lack of association between level of insight and total number of manic symptoms or with specific manic symptoms may be related to the persistence of subsyndromal symptoms in patients remitting from a manic episode.     

Intracellular calcium signalling in peripheral cells of patients with bipolar affective disorder

Summary Consistent with previous studies, elevated free intracellular calcium ion concentrations ([Ca²⁺]_i) were found in blood platelets and lymphocytes of patients with mania and bipolar depression. Incubation with an ultrafiltrate of plasma from patients with bipolar illness had no effect on intracellular calcium ion concentration in platelets from normal subjects, suggesting that elevated [Ca²⁺]_i is not due to a circulating factor. As was true in an earlier study of the effect of lithium on platelets, incubation with therapeutic levels of carbamazepine lowered [Ca²⁺]_i in lymhocytes from affectively ill patients but not controls. Increased [Ca²⁺]_i in peripheral cells may reflect a diffuse change in cellular homeostasis and may contribute to mixtures as well as rapid alternations of activity of affective, behavioral and physiologic systems in bipolar illness. Correction of the abnormality may at least be a marker of a relevant therapeutic action if it is not the action itself.     

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.     

Mania compared with unipolar depression in old age.

OBJECTIVE: The goal of this study was to clarify the meaning and importance of mania in old age. METHOD: The authors conducted a retrospective study of 50 elderly patients consecutively admitted to a private mental hospital with an index episode of mania. As a comparison group, they used 50 age- and sex-matched patients with unipolar depression. They reviewed the charts of the 100 patients for family history, clinical course, and neurological disorders. Outcome was determined by contacting patients, families, physicians, institutional settings, and vital statistics records. Survival analysis compared mortality rates. RESULTS: The manic patients had a greater familial predisposition to affective disorder and were younger at first psychiatric hospitalization. For the 20 manic patients whose first affective episode was depression, an average of 15 years elapsed before mania became manifest. Eighteen of the manic patients, compared with only four of the depressed patients, had neurological disorders. The manic patients had a significantly higher mortality rate than the depressed patients; by the end of the follow-up, 25 of the manic patients, compared with 10 of the depressed patients, had died. CONCLUSIONS: Mania appears to have a poorer prognosis and to be a more severe form of affective illness than unipolar depression. The 18 manic patients with neurological disorders seemed to have "secondary mania." Subtle cerebral changes due to aging may have been responsible for the conversion to mania in the 20 patients who experienced a long latency from first depression to onset of mania. The low frequency of early-onset mania in this study group highlights the need to differentiate early- from late-onset mania.     

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.     

Mania associated with electroconvulsive therapy

Of 94 depressed patients given electroconvulsive therapy (ECT), a manic episode developed in 6 (64%). These six patients were equally distributed across three diagnostic categories of depressive illness: primary unipolar depression, bipolar affective disorder, and schizoaffective disorder. Compared with matched controls, the patients who experienced ECT-associated mania had an earlier age of onset and a longer duration of illness. These patients also had more previous psychiatric hospitalizations. Although evidence of a direct causal relationship between the administration of ECT and the development of mania is still lacking, our data suggest that the risk of mania is higher in patients with certain clinical characteristics.     

Prolactin response to fenfluramine administration in patients with unipolar and bipolar depression and healthy controls

The hormonal response to the serotonin releasing agent/uptake inhibitor fenfluramine has been used as an indicator of central serotonin system function. The serotonergic system plays an important role in the etiology and pathogenesis of mood disorders. We compared the prolactin response to fenfluramine administration in unipolar depressed patients (major depressive disorder), depressed patients with bipolar disorder, and healthy controls. We found a trend towards a blunted prolactin response in depressed patients compared to healthy controls, after controlling for sex, family history, family history-by-gender interaction, and baseline levels. There was no significant difference between unipolar and bipolar patients in the baseline prolactin levels or the response to the fenfluramine administration. We also found a negative correlation between aggression and impulsivity scores and prolactin responses in subgroup with unipolar but not bipolar depression. Female patients with unipolar depression who had first-degree relatives with unipolar depression and normal controls had significantly higher prolactin responses than female patients with unipolar depression who did not have first-degree relatives with unipolar depression. The lack of difference in the response to fenfluramine administration between unipolar and bipolar depressed patients may indicate that overall serotonergic function in unipolar and bipolar depressed patients is similarly impaired.     

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.     

Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder

Protein kinase C (PKC) is a group of calcium and phospholipid-dependent enzymes, which plays a pivotal role in cell signaling systems. Recently accumulated evidence indicates that alterations in PKC activity play a significant role in the pathophysiology of bipolar disorder. A number of laboratories investigated the effect of mood stabilizers on the regulation of PKC activity in bipolar patients, in animals, and in cultured cells. Following chronic lithium treatment, PKC activation was significantly reduced in rat brains, as measured by the translocation of cytoplasmic PKC to the membrane compartment, or by quantitative binding of the PKC ligand, PDBu. The effect of the therapeutic concentration of lithium in attenuating PKC-dependent intracellular parameters was also demonstrated in cultured cells. More importantly, alterations in platelet PKC was shown in bipolar patients during the manic state of the illness. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity was significantly increased in manic patients, suggesting that changes in PKC may be an illness-specific marker. Interestingly, enhanced PKC activity during mania was suppressed following mood-stabilizer treatment as manic symptoms improved. In parallel to the findings in platelets, postmortem studies demonstrate that membrane-associated PKC and stimulation-induced translocation of cytosolic enzyme to the membrane were also increased in frontal cortex of bipolar patients. Other studies suggest alterations in other signal transduction mechanisms in bipolar disorder. These include alterations in G protein activation, phosphatidylinositol (PI) signaling, cyclic AMP formation, and intracellular calcium homeostasis. The alterations of PKC activity in bipolar disorder may be related to changes in these other intracellular signaling mechanisms. Alternatively, the changes of PKC activity may be the core pathology of the illness. More studies are required to further characterize the association of PKC changes with bipolar disorder, using a proper neuronal model.     

Prolactin and cortisol responses to acute intravenous clomipramine challenge in patients with mania, depression and healthy controls: evidence for reduced serotonergic responsivity

Serotonergic dysregulation has been shown to be involved in the pathophysiology of unipolar and bipolar depression. Neuroendocrine challenge tests have been extensively used to investigate serotonin functioning in the brain. Although the role of serotonin has received a great deal of attention using neuroendocrine challenge paradigms, little effort has been made to explore the role of serotonin in mania. We assessed serotonergic neuroendocrine responsivity in patients with depression (n = 22), mania (n = 11) and 15 healthy controls by measuring the prolactin (PRL) and cortisol responses to i.v. clomipramine (CMI) and searched for possible differences among the groups. Blunted PRL responses to CMI in manic and depressed patients compared to healthy controls were found. The response to CMI disclosed similar results for the 2 patient groups. No significant differences were found among the 3 subject groups in the cortisol response to CMI. The blunted PRL responses to CMI in patients with mania and depression suggest that serotonergic functioning in mania and depression is similarly impaired, at least at the level of hypothalamus-hypophysis.     

Gustatory and olfactory function in patients with unipolar and bipolar depression

Although the crucial distinction between unipolar depressive disorder and bipolar disorder is the presence of mania (or hypomania) in the course of the latter, significant differences between unipolar and bipolar depression have also been found in clinical studies. The primary aim of the present investigation was to assess pleasantness/unpleasantness ratings of chemosensory stimuli in depressed patients, including subjects with unipolar and bipolar depression. Sensory aspects (thresholds and identification abilities) of gustatory and olfactory function were also assessed. There were no major differences between a depression group, as a whole, and healthy controls in terms of gustatory and olfactory thresholds and identification abilities. Similarly, pleasantness ratings of various gustatory and olfactory stimuli did not differ between the control and depression group. Gustatory and olfactory thresholds and identification abilities did not differ between individuals with unipolar and bipolar depression. Bipolar patients tended to rate less gustatory stimuli as unpleasant and more olfactory stimuli as pleasant compared to unipolar patients. The present results suggest that: i) depression is not associated with any major deficit in sensory aspects of gustatory and olfactory function or altered hedonic ratings of chemosensory stimuli; ii) hedonic responses to chemosensory stimuli tend to be increased in bipolar as compared to unipolar depressed patients.     

The role of atypical antipsychotics in bipolar depression and anxiety disorders

Abstract:  Bipolar disorder is a complex condition that includes symptoms of mania, depression, and often anxiety. Diagnosing and treating bipolar depression is challenging, with the disorder often being diagnosed as unipolar depression. In addition, comorbid anxiety can be a significant detractor to successful outcomes, increasing symptom severity, frequency of episodes and suicide rates, and decreasing response to antidepressant therapy. Anxiety often precedes and hastens the onset of bipolar disorder, and a shared genetic etiology has been suggested. Studies have demonstrated the efficacy of atypical antipsychotics for the acute and maintenance treatment of mania. Evidence from studies in patients with treatment-resistant major depressive disorder and bipolar depression indicate that these agents may also have antidepressant effects. In open trials in patients with bipolar mania, risperidone therapy has led to significant reductions in depression scores compared with baseline. Reductions in depression scores in patients with bipolar mania have been significantly greater with olanzapine compared with placebo. In patients with bipolar depression, the combination of olanzapine and fluoxetine resulted in significant improvement in depression compared with olanzapine alone or placebo. Although little data are available on the effects of these agents on comorbid anxiety in patients with bipolar disorder, some atypical antipsychotics have demonstrated efficacy in patients with anxiety disorders, including obsessive-compulsive disorder, post-traumatic stress disorder, and generalized anxiety disorder. Thus, atypical antipsychotics represent an important therapeutic option for the treatment of bipolar disorder, providing improvements in manic, depressive, and anxiety symptoms.     

Unipolar mania: a distinct clinical entity?

Of the 241 lithium clinic patients at the New York State Psychiatric Institute with bipolar I affective disorder, 38 (15.7%) had never been hospitalized or somatically treated for depression. These "unipolar manic" patients had a significantly lower incidence of rapid cycling and suicide attempts than other bipolar I patients. No differences were found, however, in risk of illness in first-degree relatives. Lithium was an effective prophylactic agent in these patients. Some patients originally classified as "unipolar manic" were found to have depressive episodes with additional information and clinical observation. "Unipolar mania" appears to be a subgroup of bipolar I illness, but there are no data to support the hypothesis that it is a separate entity.