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BACKGROUND - Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder.
METHODS - Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change.
RESULTS - Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005).
CONCLUSIONS - Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.
OBJECTIVE - The hallmark symptom of fibromyalgia (FM) is widespread chronic pain, but most patients are also impaired due to fatigue and sleep disturbance, and there is a strong association with depression. We compared levels of activity and sleep patterns in FM patients, with and without comorbid depression, to those of normal healthy controls and depressed patients.
METHODS - Actigraphy was carried out on 16 patients with uncomplicated FM, 6 FM patients with comorbid depression, 9 patients with recurrent major depression, and 28 healthy controls over a period of 5-7 days. The means of daytime activity levels, nighttime activity levels, and percentage time spent asleep during the daytime and nighttime were calculated and compared.
RESULTS - Controls showed high levels of activity during the day and uninterrupted periods of sleep at night. Patients with FM alone showed similar levels of daytime activity, but disturbed sleep with significantly increased levels of activity at night compared to normal controls. Patients with depression alone also showed disturbed sleep compared to normal controls. However, patients with FM and comorbid depression showed the most impairment, with significantly reduced daytime activity and significantly increased daytime sleeping compared to controls, as well as more sleep interruption and movement during the night.
CONCLUSION - Actigraphy is a useful means of studying activity levels and sleep patterns and demonstrated significant differences between FM patients with and without comorbid depression.
The role of the serotonin transporter protein (STP) in the development of somatoform [corrected] disorders was addressed in a correlational study of the levels of immunoreactive STP (IR-STP) using site-specific antibodies against the least conserved (among a group of other cotransporters) epitope at the C-terminal of STP and the level of anxiety symptoms in patients with somatoform [corrected] disorders. A total of 22 patients were studied, with DSM-IV diagnoses of somatoform [corrected] disorders, along with 32 mentally healthy subjects of comparable age and sex. Immunoblotting of IR-STP from patients from healthy donors produced a diffuse band between 68 and 105 kDal and a clear narrow band at 43 kDal. The 43-kDal IR-STP protein was almost completely absent from most patients, as compared with the levels of this protein in healthy donors. This result suggests an abnormality of STP processing or, perhaps, alternative splicing of the gene encoding STP in patients with somatoform [corrected] disorders, and this appears to reflect the dysfunction in serotoninergic transmission in the CNS in these patients.
Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling.
RNA encoding the human serotonin 5-HT2C receptor (5-HT(2C)R) undergoes adenosine-to-inosine RNA editing events at five positions, resulting in an alteration of amino acids in the second intracellular loop. Several edited 5-HT(2C)Rs possess a reduced G-protein coupling efficiency compared to the completely non-edited isoform. The current studies show that the efficacy of the hallucinogenic drug lysergic acid diethylamide and of antipsychotic drugs is regulated by RNA editing, suggesting that alterations in editing efficiencies or patterns might result in the generation of a 5-HT(2C)R population differentially responsive to serotonergic drugs. An examination of the efficiencies of RNA editing of the 5-HT(2C)R in prefrontal cortex of control individuals vs. subjects diagnosed with schizophrenia or major depressive disorder revealed no significant differences in RNA editing among the three populations. However, subjects who had committed suicide (regardless of diagnosis) exhibited a statistically significant elevation of editing at the A-site, which is predicted to change the amino acid sequence in the second intracellular loop of the 5-HT(2C)R. These findings suggest that alterations in RNA editing may contribute to or complicate therapy in certain psychiatric disorders.
BACKGROUND - In nursing home residents, the use of tricyclic and other heterocyclic antidepressants is associated with an increased risk of falls. The newer selective serotonin-reuptake-inhibitor antidepressants are largely free of the side effects of the tricyclic agents thought to cause falls and so have been hypothesized to be safer for those at high risk for falls.
METHODS - We retrospectively identified an inception cohort of 2428 nursing home residents in Tennessee who were new users of tricyclic antidepressants (665 subjects), selective serotonin-reuptake inhibitors (612 subjects), or trazodone (304 subjects) or nonusers of antidepressants (847 subjects). We ascertained the number of falls during therapy and during a similar follow-up period for nonusers, then calculated the rate ratios for falls with adjustments for an extensive set of potential confounding factors.
RESULTS - The new users of each type of antidepressant had higher rates of falls than the nonusers, with adjusted rate ratios of 2.0 (95 percent confidence interval, 1.8 to 2.2) for tricyclic antidepressants, 1.8 (1.6 to 2.0) for selective serotonin-reuptake inhibitors, and 1.2 (1.0 to 1.4) for trazodone. The rate ratios increased with the daily dose for tricyclic antidepressants, reaching 2.4 (95 percent confidence interval, 2.1 to 2.8) for doses of 50 mg or more of amitriptyline or its equivalent, and for the serotonin-reuptake inhibitors, reaching 1.9 (1.7 to 2.2) for 20 mg or more of fluoxetine or its equivalent. The elevated rates of falls persisted through the first 180 days of therapy and beyond.
CONCLUSIONS - In this large study of nursing home residents, there was little difference in rates of falls between those treated with tricyclic antidepressants and those treated with selective serotonin-reuptake inhibitors. Hence, the preferential use of the newer antidepressants is unlikely to reduce the higher rate of falls among nursing home residents taking antidepressants.
Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) mediate antidepressant-sensitive clearance of 5-HT following release. Although we have been aware for decades that SERT-mediated 5-HT clearance can be modulated by exogenous agents including serotonin-selective reuptake inhibitors, amphetamines, and cocaine, we have had little reason to speculate that SERT activity was actively controlled through endogenous pathways. Recent studies indicate that SERTs are likely to be trafficked to specific plasma membrane subdomains to achieve localized clearance of 5-HT, and that the number of SERTs resident in the plasma membrane is controlled through kinase- and phosphatase-linked pathways. In particular, roles for protein kinase C and phosphatase 2A become apparent through studies with enzyme activators and inhibitors in SERT-transfected cells, where SERT proteins are rapidly phosphorylated in parallel with transporter redistribution and loss of functional uptake capacity. Based on our findings, and the studies of others in native tissues and transfected cells, we propose a model whereby SERTs are organized in a macromolecular complex in the plasma membrane that may serve to locate reuptake activity near release sites. Although many elements of this model remain hypothetical, our findings suggest a much more dynamic picture of transporter-mediated 5-HT reuptake than typically described and suggest opportunities both for the development of new SERT regulatory agents and for the identification of regulatory pathways that may be compromised in mental illness.
Form C of the Multidimensional Health Locus of Control (MHLC) scales is an 18 item, general purpose, condition-specific locus of control scale that could easily be adapted for use with any medical or health-related condition. Data from 588 patients with one of four conditions--rheumatoid arthritis, chronic pain, diabetes, or cancer--were utilized to establish the factor structure of Form C and to establish the reliability and validity of the resultant four subscales: Internality; Chance; Doctors; and Other (powerful) People. The alpha reliabilities of the subscales are adequate for research purposes. Data from the arthritis and chronic pain subjects established that the Form C subscales were moderately stable over time and possessed considerable concurrent and construct validity. Some discriminant validity of Form C with Form B of the MHLC was also demonstrated.
Data were collected on six large multigenerational pedigrees, four ascertained through a proband with major depression and two ascertained through a proband with a bipolar form of illness. Diagnoses were made using the SADS-L structured interview and Research Diagnostic Criteria (RDC). Complex segregation analyses were conducted on the bipolar and the major depression pedigree sets using a model allowing for both major locus and polygenic inheritance; in these analyses a variety of diagnostic schemes and assumptions concerning the lifetime population prevalence were examined. Linkage analyses on standard markers were conducted using parameters for transmission of susceptibility to illness derived from the segregation analyses. Results of the segregation analyses were quite sensitive to the diagnostic and prevalence assumptions. In the pedigrees ascertained through probands with a bipolar form of illness, we were unable to discriminate between major gene and polygenic inheritance. The data were compatible with Mendelian major gene transmission of susceptibility to illness when bipolar and schizoaffective manic diagnoses were considered as affected and the lifetime population prevalence was between 0.04 and 0.06. Outside this narrow prevalence range, or when additional diagnoses, such as major depression or hypomania, were included as expressions of liability to disease, major gene transmission of susceptibility to disease could be rejected. Similarly, in the pedigrees ascertained through probands with major depression, it was not generally possible to discriminate between major gene and polygenic transmission of susceptibility to illness. For a diagnostic scheme including only major depression as a manifestation of susceptibility to illness, there was a narrow range of lifetime population prevalence values (female prevalence ranging from 0.20 to 0.25, male prevalence set to 1/2 female prevalence) which yielded results compatible with major gene transmission. Linkage analyses for all markers yielded negative or inconclusive results. In one bipolar pedigree a lod score of 1.65 was found with a marker in chromosome 1 recommending further studies of this chromosome.
We derived a model of appraisal, coping, and adaptation in patients with rheumatoid arthritis (RA) from the more general theory of Lazarus and Folkman (1984) and examined this model using a longitudinal data set spanning 4 years and involving 239 RA patients (of whom 157 contributed to the primary analyses, with the remainder contributing to various follow-up analyses). This model attempted to identify the short- and long-term adaptational consequences of coping as well as the antecedents (appraisals, beliefs, social support, disease activity, etc.) that promote particular coping styles. Interrelations among the variables were examined using path-analytic techniques. Many observed relations were consistent with the model. Significant relations were subjected to more stringent analyses examining the ability of hypothesized causal variables to predict changes in outcome variables 1 year later. These analyses provided additional support for many observed relations and suggested the existence of a vicious cycle involving helplessness appraisals, passive coping with pain, and psychosocial impairment that promotes maladaptation in the face of RA. Theoretical implications, strengths, and limitations of the study are discussed.