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Biomedical subjects

J C Soares

Publications and source records attributed to J C Soares.

At least 37 records · Page 2Linked to original sources
PubMed2001

Anatomical MRI study of basal ganglia in bipolar disorder patients.

This study examined possible anatomical abnormalities in basal ganglia structures in bipolar disorder patients. Caudate and putamen gray matter volumes, and globus pallidus total volume were measured with magnetic resonance imaging (MRI) in 22 DSM-IV bipolar patients (age+/-S.D.=36+/-10 years; eight drug-free and 14 lithium monotherapy patients) and 22 matched healthy control subjects (age+/-S.D.=38+/-10 years). No significant differences were found between bipolar patients and healthy control subjects for any of the basal ganglia measures (t-tests, P>0.05). Age was inversely correlated with left putamen volumes in patients (R=-0.44, P=0.04), but not in healthy control subjects (R=-0.33, P=0.14). Older patients (>36 years old) had a significantly larger left globus pallidus than younger ones (< or =36 years old) (ANOVA, P=0.01). In a multiple regression analysis, after entering age as independent variable, the length of illness predicted smaller left putamen volumes, explaining 10.4% of the variance (F=4.07, d.f.=2, P=0.03). No significant effects of episode type, number of prior episodes, or gender were found in any basal ganglia measurements (ANOVA, P>0.05). In conclusion, our findings indicate that the basal ganglia may be anatomically preserved in bipolar patients. This is in contrast to available findings for unipolar disorder. However, our findings also suggest that age and length of illness may have significant effects on basal ganglia structures in bipolar patients, which may be more pronounced among bipolar I patients, and of relevance for the pathophysiology of the disorder.

Adult↗
PubMed2001

Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T.

BACKGROUND: This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS: Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS: The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS: This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

Adult↗
PubMed2001

Increased platelet membrane phosphatidylinositol-4,5-bisphosphate in drug-free depressed bipolar patients.

Prior investigations in bipolar disorder patients have suggested abnormalities in the cellular phosphoinositide second messenger system. This study was conducted to examine the levels of platelet membrane phosphoinositides in drug-free bipolar patients in the depressed state (n=9) and healthy controls (n=19). Bipolar patients had significantly increased levels of platelet membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)) compared to healthy individuals (0.67+/-0.14 and 0.44+/-0.17%, respectively, t-test=3.71, d.f.=26, P=0.001). No significant differences in the levels of phosphatidylinositol-4-phosphate (PIP) (0.65+/-0.17 and 0.58+/-0.20%, respectively, t-test=1.02; d.f.=26; P=0.32) or phosphatidylinositol (PI) (5.92+/-1.23 and 5.56+/-1.45%, respectively, t-test=0.68; d.f.=26; P=0.51) were found. These findings provide the first demonstration of increased PIP(2) platelet levels in bipolar patients in the depressed state, and provide additional evidence that the phosphoinositide second messenger system may be a site of abnormality in bipolar disorder.

Adult↗
PubMed2001

Perspectives on the use of anticonvulsants in the treatment of bipolar disorder.

The authors reviewed the available literature on the efficacy of carbamazepine, valproate, and other newer anticonvulsants for the treatment of bipolar disorder. A comprehensive Medline search was conducted, and all uncontrolled and controlled reports on anticonvulsants used for the treatment of bipolar patients were identified. Carbamazepine and valproate have been shown to be effective in the acute treatment of bipolar disorder, and are the first-choice treatments for lithium-refractory patients. While the efficacy of these drugs in the acute treatment of the illness has been satisfactorily documented, double-blind randomized studies are still necessary to evaluate the long-term effectiveness of both anticonvulsants. Patients on a mixed state and rapid cyclers seem to respond better to valproate and carbamazepine than to lithium. The preliminary data evaluating the efficacy of newer anticonvulsants, such as gabapentin, lamotrigine, and topiramate in bipolar patients is still limited, but some of the available findings are promising, and these new agents may represent appropriate third choices for refractory bipolar individuals. Double-blind, controlled studies with the newer anticonvulsants are still largely unavailable, and it will be necessary to evaluate their acute and prophylactic mood-stabilizing effects. The prospects for future therapeutic advances in this area are also discussed.

Anticonvulsants↗
PubMed2001

Differential effects of age on brain gray matter in bipolar patients and healthy individuals.

This study examined possible differences in total gray and white matter brain content in bipolar patients and healthy individuals, and their relationship with age. 22 DSM-IV bipolar patients and 22 healthy controls underwent a 1.5-tesla Spoiled Gradient Recalled Acquisition (SPGR) MRI. Evaluators blind to patients' identities measured total brain, gray and white matter volumes using a semi-automated software. No differences were found for total brain volume, gray matter or white matter volumes between bipolar patients and healthy controls (MANCOVA, age as covariate, p > 0.05). Age was inversely correlated with total gray matter volume in patients (r = -0.576, p = 0.005), but not in controls (r = -0.193, p = 0.388). Our findings suggest that any existing gray matter deficits in bipolar disorder are likely to be localized to specific brain regions, rather than generalized. The inverse correlation between age and brain gray matter volumes in bipolar patients, not present in healthy controls, in this sample of mostly middle-aged adults, could possibly indicate more pronounced age-related gray matter decline in bipolar patients, and may be of potential relevance for the pathophysiology of the disorder.

Adolescent↗
PubMed2000

Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study.

This study examined the hypothesis that lithium inhibits the PI signaling pathway in humans during in vivo administration by concurrently measuring PKC isozymes and platelet membrane phosphoinositides in lithium-treated patients and healthy individuals. The platelet membrane and cytosolic levels of PKC alpha, beta I, beta II, delta, and epsilon were measured using Western blotting. The relative platelet membrane contents of phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP(2)) were measured with two-dimensional thin-layer chromatography. Nine euthymic lithium-treated bipolar subjects and 11 healthy control subjects were studied. Compared to control subjects, lithium-treated bipolar patients had significantly lower levels of cytosolic PKC alpha isozyme (t-test=-3.24, d.f.=17, P=0.01) and PIP(2) platelet membrane levels (t-test=-2.51, d.f.=18, P=0.02), and a trend toward reduced levels of cytosolic PKC beta II isozyme (t=-2.17, d.f.=17, P=0.05). There was no significant correlation between PIP(2) and any of the PKC isozymes. These preliminary findings suggest that chronic lithium treatment may decrease the levels of both cytosolic PKC alpha isozyme and membrane PIP(2) in platelets of bipolar disorder patients.

Adult↗
PubMed2000

Effects of lithium on platelet membrane phosphoinositides in bipolar disorder patients: a pilot study.

RATIONALE: In vitro and in vivo animal studies suggest that the intracellular phosphatidylinositol (PI) pathway is an important target for the effects of lithium. OBJECTIVES: We conducted a preliminary study to examine the in vivo effects of lithium treatment on platelet membrane phosphoinositides in bipolar disorder subjects, in an attempt to examine further the hypothesis that lithium has significant in vivo effects on the PI pathway in these patients. METHODS: We quantitated PI, phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2) in platelet membranes of seven subjects (five male, two female; mean age= 27.9+/-5.7 years), initially while they were unmedicated, and a second time after at least 21 days of lithium treatment (mean+/-SD=28.7+/-7.1 days). RESULTS: The mean+/-SD values for PI were 5.63+/-2.25% and 5.21+/-1.06%; for PIP 0.68+/-0.20% and 0.55+/-0.11%; and for PIP2 0.60+/-0.21% and 0.38+/-0.15%, before and after lithium treatment, respectively. The decrease in PIP2 values after lithium treatment was statistically significant (Wilcoxon signed ranks test, Z=-2.37, P=0.02). CONCLUSION: This longitudinal study suggests that therapeutic doses of lithium significantly decrease platelet membrane PIP2 levels in vivo in bipolar disorder subjects, which may be related to lithium's mechanism of action in bipolar disorder.

Adult↗
PubMed2000

Brain lithium measurements with (7)Li magnetic resonance spectroscopy (MRS): a literature review.

7Li magnetic resonance spectroscopy (MRS) has been successfully used in recent years as a new tool to measure brain tissue lithium concentrations in vivo. After demonstration of its feasibility in animal studies over a decade ago, human investigations have characterized the brain pharmacokinetics of lithium. Preliminary studies have investigated brain pharmacokinetic correlates of clinical response in the treatment of bipolar disorder patients, with indication of possible clinical relevance of 7Li MRS measures. In this paper we reviewed the accumulated literature in this area, and discuss possible directions for this research in the context of preliminary studies conducted by our group that demonstrated the feasibility of 7Li MRS at 3 T.

Animals↗
PubMed2000

Equilibrium modeling of 5-HT(2A) receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm.

[(18)F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT(2A)) receptors. The deuterium substitution of both of the 2'-hydrogens of altanserin ([(18)F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [(18)F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an (18)F-labeled tracer (T(1/2) 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [(18)F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [(18)F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V(')(3) (ratio of specific uptake to total plasma parent concentration) and the binding potential V(3) (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [(18)F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [(18)F]deuteroaltanserin and suggest that it may be superior to [(18)F]altanserin as a PET radioligand.

Adolescent↗
PubMed2000

Valproate treatment and the risk of hyperandrogenism and polycystic ovaries.

Long-term administration of valproate to women with epilepsy has been suggested to result in increased risk of hyperandrogenism and polycystic ovaries. In preliminary reports involving patients treated for several years, the reported rates were as high as 43% for polycystic ovaries and 17% for hyperandrogenism. In particular, when therapy started before the age of 20 years, the rates of either one of these complications were as high as 80%. Surprisingly, these reports have been relatively ignored in the psychiatric literature to date. As increasing numbers of bipolar patients are in long-term treatment with valproate, there is an important need for further research that clarifies the relationship between long-term administration of valproate and other mood stabilizers and the potential development of reproductive endocrinologic abnormalities, and for increased awareness among clinicians and patients of the unknown potential for these worrisome side-effects.

Adult↗
PubMed2000

Recent advances in the treatment of bipolar mania, depression, mixed states, and rapid cycling.

New pharmacological agents for the treatment of bipolar disorder are under investigation. Some of the new potential treatments attempt to target specific clinical conditions that constitute particular challenges in the management of bipolar individuals. Typical cases of mania traditionally respond well to lithium, but atypical cases, in particular patients with mixed episodes, tend to respond poorly. The pharmacological treatment of bipolar depression is complicated by the phenomenon of rapid cycling, which may make the clinical management of these patients considerably difficult. New therapeutic agents, including new anticonvulsants, atypical antipsychotics, and calcium channel blockers are currently being examined, and bring the promise of substantial advances in the pharmacological management of bipolar patients. Recent developments in this area are reviewed, with a focus on alternatives for the treatment of refractory mania, bipolar depression, mixed states, and rapid cycling patients.

Anticonvulsants↗
PubMed2000

Morphological characteristics of neuromuscular junctions of the opossum (Didelphis albiventris) extraocular muscles: a scanning-electron-microscopic study.

Three types of neuromuscular junctions were described in the extraocular muscles of the opossum. The present study demonstrates the three-dimensional characteristics of these neuromuscular junctions after HCl connective tissue digestion. Adult opossum of both sexes were used and the neuromuscular junctions of the extraocular muscles were examined after removal of the intramuscular connective tissue and basal layer. This material was examined with a scanning electron microscope. Two types of 'en plaque' neuromuscular junction were described: the continuous type revealed elongated and branched primary synaptic grooves separated from each other by sarcolemma protuberances with different sizes, and the discontinuous or punctiform type which presents very shallow and discontinuous grooves when compared with the former. The multiple neuromuscular junctions were observed as two or three junctions associated with the same muscular fiber. The multiple junctions were present in thin fibers (around 11 microm caliber); the en plaque junctions were associated with large diameter fibers (around 21 microm). This study confirms and reveals the detailed morphological characteristics of the three neuromuscular junction types previously described by transmission electron microscope in the extraocular muscles of opossum.

Animals↗
PubMed2000

The psychopharmacologic specificity of the lithium ion: origins and trajectory.

This article examines the development of lithium therapy since its dramatic introduction into psychiatry in 1949. Since that time, lithium has been examined in the treatment of a variety of neuropsychiatric conditions, but it is in the treatment of bipolar disorder that it is most effective. This suggests that it has specificity in the treatment of this disorder. These findings are very relevant as they suggest that understanding the mechanism of action of lithium in bipolar disorder may hold keys to elucidating its pathophysiology and to developing newer and more effective treatments. We review the published data on the effectiveness of lithium in bipolar disorder and various neuropsychiatric conditions and also the available data on anticonvulsants and newer therapeutic agents in the treatment of this condition.

Anticonvulsants↗
PubMed1999

[123I]Iomazenil SPECT benzodiazepine receptor imaging in schizophrenia.

Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [123I]iomazenil was used with a constant infusion paradigm to measure the BZR V3-p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of 'absolute' values of V3-p with no normalization for total brain uptake, the schizophrenic patients showed no significant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V3-p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V3-p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V3-p were observed between patients and control subjects, except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.

Adult↗
PubMed1999

Neurochemical brain imaging investigations of schizophrenia.

Neurochemical brain imaging methods developed over the past 20 years offer significant promise for elucidating the biochemical underpinnings of schizophrenia. The two general methodologies used for these studies have been: 1) radiotracer imaging: PET (positron emission tomography) and SPECT (single photon emission computed tomography); and 2) NMR (nuclear magnetic resonance) imaging: fMRI (functional magnetic resonance imaging) and MRS (magnetic resonance spectroscopy). Despite conflicting findings, striatal D2 receptor density may be elevated in some, but not all patients. Elevated synthesis, and increased release of dopamine after amphetamine challenge have also been reported. Imaging of cortical 5-HT2A receptors suggests that this system is unaffected, in conflict with findings of postmortem studies. Although prior postmortem studies suggested an increase in cortical GABAA receptors, three SPECT studies have found no significant changes. MRS studies have shown decreased levels of NAA (N-acetyl-aspartate) moieties in hippocampus and frontal cortex of schizophrenic patients, which is consistent with the reported loss of neurons and neuropil in postmortem brains. In conclusion, developments in radiotracer and NMR imaging have provided promising leads to the biochemical abnormalities associated with schizophrenia. Future significant understanding is likely to occur with the development of new probes and enhanced instrument technology, when applied with an appreciation of the heterogeneity of the disorder and the need for careful clinical assessment of patients.

Aspartic Acid↗
PubMed1999

Reproducibility of in vivo measures of platelet membrane phospholipids in human subjects.

Membrane phospholipid abnormalities in the brain neurons may be implicated in the pathophysiology of neuropsychiatric disorders. In the absence of methods to directly examine the levels of brain membrane phospholipids in vivo in human subjects, peripheral cells and platelets have been used as models in this field. We previously reported a method to determine the relative amounts of eight individual platelet membrane phospholipid classes using two-dimensional thin-layer chromatography, and scanning-laser densitometry (Mallinger et al., 1993). Here we report the test/retest reproducibility of these platelet membrane phospholipid measures in healthy human subjects (n = 12) who were studied on two different occasions separated by a 3-week interval. The mean intra-subject coefficients of variation were 3.1-18%, and the intra-class correlation coefficients (ICCs) were 0.41-0.68. These findings are consistent with a low to moderate variability, and moderate reliability of these individual platelet membrane phospholipid measures over the period studied. When this method is applied for longitudinal studies of psychiatric populations, the degree of variability has to be considered in the interpretation of the results.

Adult↗
PubMed1999

Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans.

Changes of central type GABA(A)/benzodiazepine receptors during 24-day per-oral administration of alprazolam (2 mg/day) were measured with single photon emission computed tomography (SPECT) in nine healthy human subjects. Receptor densities were measured on days -4 (baseline), 3, 10, 17 and 24. Comparison of baseline and day 3 SPECT images was used to assess receptor occupancy; comparisons of the four scans on medication were used to assess alterations in receptor levels. Clinical effects were evaluated by subjective ratings of mood and the Hopkins verbal learning test. Alprazolam induced sedation associated with a 16% receptor occupancy. Unoccupied receptor levels decreased 10% from day 3 to day 10 but then normalized to baseline values by day 17. Clinical effects showed corresponding changes 1-2 weeks after the changes in the receptor. Thus, the decrease of benzodiazepine receptor densities may be one of the major mechanisms for tolerance development in humans.

Administration, Oral↗