Stabilization treatment of remitted psychotic depression: the STOP-PD study.

OBJECTIVE: We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD). METHODS: Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination. RESULTS: The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change. CONCLUSION: Continuation of acute treatment was associated with stability of remission.

Abdominal obesity and hip fracture: results from the Nurses' Health Study and the Health Professionals Follow-up Study.

UNLABELLED: Abdominal obesity might increase fracture risk. We studied the prospective associations between waist circumference, waist-to-hip ratio, and hip fracture. The indicators of abdominal obesity were associated with increased hip fracture risk in women, but not in men. The increased risk was restricted to women with low physical activity. INTRODUCTION: Low weight is an established risk factor for osteoporosis and hip fracture. However, the association between fat tissue, muscle, and bone is complex, and abdominal obesity might increase fracture risk. We studied the prospective associations between indicators of abdominal obesity and hip fracture in two large US cohorts. METHODS: At baseline in 1986 and through biennial follow-up, information on hip fracture and potential risk factors was collected in 61,677 postmenopausal women and 35,488 men above age 50. Waist and hip circumferences were reported at baseline and updated twice. RESULTS: During follow-up, 1168 women and 483 men sustained a hip fracture. After controlling for known risk factors, there was a significant association in women between increasing waist circumference and hip fracture (RR per 10-cm increase 1.13 (95 % CI 1.04-1.23) and between increasing waist-to-hip ratio and hip fracture (RR per 0.1 unit increase 1.14 (95 % CI 1.04-1.23), but these associations were not seen in men. In women, both measures interacted with physical activity. Those in the highest (≥0.90) versus lowest (<0.75) category of waist-to-hip ratio had increased risk of hip fracture if their activity was less than the population median (RR = 1.61, 95 % CI 1.18-2.19) but not if their activity was higher (RR = 1.00, 95 % CI 0.72-1.40). A similar pattern was found for waist circumference. CONCLUSION: Indicators of abdominal obesity were associated with increased hip fracture risk after controlling for BMI in women. The increased risk was restricted to women with low physical activity. In men, no significant associations were found.

Rating scales measuring the severity of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD. METHOD: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed. RESULTS: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD. CONCLUSION: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice.

Measuring psychotic depression.

OBJECTIVE: Psychotic depression (PD) is a highly debilitating condition, which needs intensive monitoring. However, there is no established rating scale for evaluating the severity of PD. The aim of this analysis was to assess the psychometric properties of established depression rating scales and a number of new composite rating scales, covering both depressive and psychotic symptoms, in relation to PD. METHOD: The psychometric properties of the rating scales were evaluated based on data from the Study of Pharmacotherapy of Psychotic Depression. RESULTS: A rating scale consisting of the 6-item Hamilton melancholia subscale (HAM-D6 ) plus five items from the Brief Psychiatric Rating Scale (BPRS), named the HAMD-BPRS11 , displayed clinical validity (Spearman's correlation coefficient between HAMD-BPRS11 and Clinical Global Impression - Severity (CGI-S) scores = 0.79-0.84), responsiveness (Spearman's correlation coefficient between change in HAMD-BPRS11 and Clinical Global Impression - Improvement (CGI-I) scores = -0.74--0.78) and unidimensionality (Loevinger's coefficient of homogeneity = 0.41) in the evaluation of PD. The HAM-D6 fulfilled the same criteria, whereas the full 17-item Hamilton Depression Scale failed to meet criteria for unidimensionality. CONCLUSION: Our results suggest that the HAMD-BPRS11 is a more valid measure than pure depression scales for evaluating the severity of PD.

Homophilic binding of PTP mu, a receptor-type protein tyrosine phosphatase, can mediate cell-cell aggregation.

The receptor-like protein tyrosine phosphatase, PTPmu, displays structural similarity to cell-cell adhesion molecules of the immunoglobulin superfamily. We have investigated the ability of human PTPmu to function in such a capacity. Expression of PTPmu, with or without the PTPase domains, by recombinant baculovirus infection of Sf9 cells induced their aggregation. However, neither a chimeric form of PTPmu, containing the extracellular and transmembrane segments of the EGF receptor and the intracellular segment of PTPmu, nor the intracellular segment of PTPmu expressed as a soluble protein induced aggregation. PTPmu mediates aggregation via a homophilic mechanism, as judged by lack of incorporation of uninfected Sf9 cells into aggregates of PTPmu-expressing cells. Homophilic binding has been demonstrated between PTPmu-coated fluorescent beads (Covaspheres) and endogenously expressed PTPmu on MvLu cells. Additionally the PTPmu-coated beads specifically bound to a bacterially expressed glutathione-S-transferase fusion protein containing the extracellular segment of PTPmu (GST/PTPmu) adsorbed to petri dishes. Covaspheres coated with the GST/PTPmu fusion protein aggregated in vitro and also bound to PTPmu expressed endogenously on MvLu cells. These results suggest that the ligand for this transmembrane PTPase is another PTPmu molecule on an adjacent cell. Thus homophilic binding interactions may be an important component of the function of PTPmu in vivo.

Crystal structure of human protein tyrosine phosphatase 1B.

Protein tyrosine phosphatases (PTPs) constitute a family of receptor-like and cytoplasmic signal transducing enzymes that catalyze the dephosphorylation of phosphotyrosine residues and are characterized by homologous catalytic domains. The crystal structure of a representative member of this family, the 37-kilodalton form (residues 1 to 321) of PTP1B, has been determined at 2.8 A resolution. The enzyme consists of a single domain with the catalytic site located at the base of a shallow cleft. The phosphate recognition site is created from a loop that is located at the amino-terminus of an alpha helix. This site is formed from an 11-residue sequence motif that is diagnostic of PTPs and the dual specificity phosphatases, and that contains the catalytically essential cysteine and arginine residues. The position of the invariant cysteine residue within the phosphate binding site is consistent with its role as a nucleophile in the catalytic reaction. The structure of PTP1B should serve as a model for other members of the PTP family and as a framework for understanding the mechanism of tyrosine dephosphorylation.

Autophosphorylation of protein kinase C at three separated regions of its primary sequence.

The major autophosphorylation sites of the rat beta II isozyme of protein kinase C were identified. The modified threonine and serine residues were found in the amino-terminal peptide, the carboxyl-terminal tail, and the hinge region between the regulatory lipid-binding domain and the catalytic kinase domain. Because this autophosphorylation follows an intrapeptide mechanism, extraordinary flexibility of the protein is necessary to phosphorylate the three regions. Comparison of the sequences surrounding the modified residues showed no obvious recognition motif nor any similarity to substrate phosphorylation sites, suggesting that proximity to the active site may be the primary criterion for their phosphorylation.

Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B.

The crystal structures of a cysteine-215-->serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational change of a surface loop that created a phosphotyrosine recognition pocket and induced a catalytically competent form of the enzyme. The phosphotyrosine side chain is buried within the period and anchors the peptide substrate to its binding site. Hydrogen bonds between peptide main-chain atoms and the protein contribute to binding affinity, and specific interactions of acidic residues of the peptide with basic residues on the surface of the enzyme confer sequence specificity.

Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST.

PTP-PEST is a ubiquitously expressed, cytosolic, mammalian protein tyrosine phosphatase (PTP) which exhibits high specific activity in vitro. We have investigated the substrate specificity of PTP-PEST by a novel substrate-trapping approach in combination with in vitro dephosphorylation experiments. We initially identified a prominent 130-kDa tyrosine-phosphorylated protein in pervanadate-treated HeLa cell lysates which was preferentially dephosphorylated by PTP-PEST in vitro. In order to identify this potential substrate, mutant (substrate-trapping) forms of PTP-PEST were generated which lack catalytic activity but retain the ability to bind substrates. These mutant proteins associated in stable complexes exclusively with the same 130-kDa protein, which was identified as p130(cas) by immunoblotting. This exclusive association was observed in lysates from several cell lines and in transfected COS cells, but was not observed with other members of the PTP family, strongly suggesting that p130(cas) represents a major physiologically relevant substrate for PTP-PEST. Our studies suggest potential roles for PTP-PEST in regulation of p130(cas) function. These functions include mitogen- and cell adhesion-induced signalling events and probable roles in transformation by various oncogenes. These results provide the first demonstration of a PTP having an inherently restricted substrate specificity in vitro and in vivo. The methods used to identify p130(cas) as a specific substrate for PTP-PEST are potentially applicable to any PTP and should therefore prove useful in determining the physiological substrates of other members of the PTP family.

Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo.

The p210 bcr-abl protein tyrosine kinase (PTK) appears to be directly responsible for the initial manifestations of chronic myelogenous leukemia (CML). In contrast to the extensive characterization of the PTK and its effects on cell function, relatively little is known about the nature of the protein tyrosine phosphatases (PTPs) that may modulate p210 bcr-abl-induced signalling. In this study, we have demonstrated that expression of PTP1B is enhanced specifically in various cells expressing p210 bcr-abl, including a cell line derived from a patient with CML. This effect on expression of PTP1B required the kinase activity of p210 bcr-abl and occurred rapidly, concomitant with maximal activation of a temperature-sensitive mutant of the PTK. The effect is apparently specific for PTP1B since, among several PTPs tested, we detected no change in the levels of TCPTP, the closest relative of PTP1B. We have developed a strategy for identification of physiological substrates of individual PTPs which utilizes substrate-trapping mutant forms of the enzymes that retain the ability to bind to substrate but fail to catalyze efficient dephosphorylation. We have observed association between a substrate-trapping mutant of PTP1B (PTP1B-D181A) and p210 bcr-abl, but not v-Abl, in a cellular context. Consistent with the trapping data, we observed dephosphorylation of p210 bcr-abl, but not v-Abl, by PTP1B in vivo. We have demonstrated that PTP1B inhibited binding of the adapter protein Grb2 to p210 bcr-abl and suppressed p210 bcr-abl-induced transcriptional activation that is dependent on Ras. These results illustrate selectivity in the effects of PTPs in a cellular context and suggest that PTP1B may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.

Purification and crystallization of the catalytic domain of human protein tyrosine phosphatase 1B expressed in Escherichia coli.

The amino-terminal 321 residues encoding the catalytic domain of human protein tyrosine phosphatase 1B (molecular mass 37 kDa) has been expressed in Escherichia coli, purified to homogeneity and crystallized. The crystals diffract to 2.4 A resolution when exposed to synchrotron radiation and belong to space group P3(1)21 (or its enantiomorph P3(2)21) with a = 88.4 A, b = 88.4 A, c = 104.0 A, alpha = beta = 90.0 degrees, gamma = 120.0 degrees. There is one molecule of protein tyrosine phosphatase 1B per asymmetric unit and the crystal form is suitable for the determination of the atomic structure of the enzyme.

Epidemiology and comorbidity of anxiety disorders in the elderly.

OBJECTIVE: The author reviewed the epidemiology and comorbidity of anxiety disorders in the elderly. METHOD: Data from 1970 onward were obtained through a computerized literature search, a review of Index Medicus, and the bibliographies of retrieved articles. Eight random-sample community surveys of anxiety disorders in persons 60 years of age or older were identified. Studies relating to the comorbidity of late-life anxiety and depression, dementia, alcoholism, and medical illness were also reviewed. RESULTS: The majority of studies showed that anxiety disorders are less common in the elderly than in younger adults. Generalized anxiety disorder and phobias account for most anxiety in late life; panic disorder is rare. Agoraphobia, and possibly obsessive-compulsive disorder in females, may occur as a primary disorder for the first time in old age, whereas simple phobia, obsessive-compulsive disorder in males, and panic disorder either persist from younger years or arise in the context of another psychiatric or medical disorder. There is considerable comorbidity of geriatric depression and generalized anxiety disorder and phobias, although the depression usually goes untreated or is inappropriately treated with benzodiazepines. The rate of comorbidity of anxiety and medical illness and alcoholism is lower in the elderly than in younger persons. CONCLUSIONS: Epidemiologic data on the prevalence of posttraumatic stress disorder (PTSD) and the first occurrence of generalized anxiety disorder and PTSD in late life are still needed. Further comorbidity studies are needed to determine the extent to which anxiety arises secondary to depression, as well as the optimal treatment and prognosis for this mixed state.

Recurrence of first-episode geriatric depression after discontinuation of maintenance antidepressants.

OBJECTIVE: Later age at onset of depression appears to be a risk factor for early recurrence. Therefore, the authors examined the 2-year outcomes of elderly patients with first-episode major depression following discontinuation of their maintenance antidepressant medication. METHOD: The study group consisted of 21 elderly patients who had recovered from a first lifetime episode of major depression. They had taken maintenance antidepressant medication for 2 years and had not had a relapse or recurrence during that time. The antidepressant was then withdrawn, and patients were followed for another 2 years or until recurrence, whichever occurred first. RESULTS: The cumulative probability of suffering a recurrence of major depression was 61%. Eleven of the 12 patients who suffered a recurrence restarted the antidepressant, and 10 responded. CONCLUSIONS: Elderly patients with first-episode major depression were at high risk of recurrence following discontinuation of maintenance antidepressant medication. However, the vast majority of patients who experienced a recurrence responded to reinstated treatment.

Two-year outcome of psychotic depression in late life.

OBJECTIVE: The purpose of this study was to determine whether elderly patients with psychotic depression differed in long-term outcome from patients with nonpsychotic depression. METHOD: The study group consisted of 19 patients with psychotic major depression who had responded to ECT (N = 15), nortriptyline and perphenazine (N = 2), or nortriptyline, perphenazine, and adjunctive lithium (N = 2) and 68 nonpsychotic depressed patients who had responded to either nortriptyline alone (N = 61) or nortriptyline and lithium (N = 7). All patients were maintained on regimens of full-dose nortriptyline. When prescribed for the index episode, adjunctive lithium was also maintained, but perphenazine was withdrawn 16 weeks after response. Patients were followed on a monthly basis for 2 years or until relapse or recurrence, whichever occurred first. RESULTS: Patients with psychotic depression had a substantially higher frequency of relapse or recurrence of depression and a shorter time to these events than nonpsychotic depressed patients. At index assessment, patients with psychosis were more severely depressed and had had more prior episodes of depression, but these factors did not account for the difference in outcome between the two groups. Furthermore, before entering the study, none of the psychotic patients had received adequate treatment for the index episode of depression, and so their poor outcome could not be attributed to prior treatment resistance. CONCLUSIONS: Even when they achieved remission and were maintained on a regimen of full-dose antidepressant medication, older patients with psychotic depression were at greater risk of relapse or recurrence than were their nonpsychotic counterparts. In particular, continuation/maintenance treatment with tricyclic monotherapy following response to ECT had limited efficacy in this group of patients. These findings raise important questions about the optimal treatment of psychotic depression in late life.

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Compensatory regulation in metabolic pathways--responses to increases and decreases in citrate synthase levels.

The level of citrate synthase was varied in Escherichia coli by recombinant DNA methods to elucidate regulatory interactions between the individual steps of the citric acid cycle. The effects of overproduction and underproduction of citrate synthase were assessed by measuring metabolite levels, rates of carbon flow, the phosphorylation state of isocitrate dehydrogenase, and the growth rate of the culture. This analysis revealed that the levels of citrate synthase and isocitrate dehydrogenase activity are co-ordinated for efficient growth on acetate. When citrate synthase was overproduced the isocitrate dehydrogenase reaction became rate limiting and prevented large increases in the flux through the citric acid cycle. Furthermore, changes in the level of citrate synthase were found to modulate the phosphorylation state of isocitrate dehydrogenase which regulates the distribution of carbon flow between the citric acid cycle and the glycoxylate shunt. These adjustments allowed the organism to maintain a relatively constant metabolic state despite changes in the level of a central metabolic enzyme. The interplay between citrate synthase and isocitrate dehydrogenase illustrates how living systems can compensate for variations in their internal environment.

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects.

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Urinary incontinence associated with dementia.

Urinary incontinence is common in patients with dementia and is more prevalent in demented than in nondemented older individuals. It occurs with equal or greater frequency in males than in females, and this contrasts with the female preponderance in community-based, general older populations. Since the etiology of incontinence in dementia is multifactorial, a comprehensive assessment of factors within and outside the lower urinary tract is essential. A careful clinical evaluation is sufficient to guide treatment in most cases. Further research is needed to determine the role of simple cystometry and more complex urodynamic investigation in these patients. Research on the management of urinary incontinence in demented patients has focused almost exclusively on toileting programs and drug treatments for detrusor hyperactivity. To date, anticholinergic and antispasmodic medications have not been shown to be effective in treating incontinence in demented persons. However, the few studies undertaken have been in the most severely mentally and physically deteriorated patients, and it is possible that these medications have greater efficacy in less impaired individuals. Prompted voiding regimens have been shown to reduce incontinence by an average of 32% and appear to be a useful approach in managing incontinence in some of these patients. However, unless staff management systems are employed, staff compliance with these programs diminishes with time and the labor costs involved may limit their applicability in nursing homes. Patients who are the most severely cognitively impaired, least mobile, and have the greatest frequency of incontinence derive the least benefit from toileting programs, and palliative measures may be more appropriate in these cases.

Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression.

Psychomotor retardation, characterized by changes in speech, motility and cognition, is common in major depression. It is also a cardinal feature of subcortical disorders such as Parkinson's disease (PD). Based on this observation and other data it has been hypothesized that the retardation of depression is related to mesolimbic-nigrostriatal dysfunction. To further test this hypothesis, speech articulation in major depression was compared to that in PD, where disordered articulation is related to bradykinesia and rigidity caused by striatal dopamine depletion. Thirty subjects with major depression were compared with 30 patients with PD and 31 normal controls on 3 acoustic measures of articulation. Major depression and PD groups had significantly shortened voice onset time and decreased second formant transition compared to controls, and major depression also had increased spirantization. There were no differences between the depression and PD groups on any of the acoustic measures. These findings provide indirect support for the hypothesis that nigrostriatal dysfunction is related to psychomotor slowing in major depression.

Trends in black/white differences in current smoking among 18- to 24-year-olds in the United States, 1983-1993.

OBJECTIVES: A study was undertaken to analyze the independent relationship between race (black/white) and cigarette smoking among 18- to 24-year-olds in the United States, 1983-1993. METHODS: An 11-year analysis of cross-sectional national surveys was used in the study. Odds ratio for current smoking among black-surveyed subjects (vs. whites) was determined. RESULTS: The multiple logistic regression-derived odds ratio (OR) for current smoking for blacks aged 18 to 24 years, vs. whites, decreased from 0.69 (95% CI 0.53, 0.89) in 1983 to 0.26 (95% CI 0.17, 0.42) in 1993. The combined-years model predicted a decrease in OR for blacks from 0.82 in 1983 to 0.30 in 1993, adjusted for sex, age, education, poverty status, and geographic region. CONCLUSION: From 1983 to 1993, blacks aged 18 to 24 years became decreasingly at risk to be smokers, compared to whites, even after adjustment for confounding factors. Young blacks have been more resistant than young whites to begin smoking in recent years. Understanding reasons behind this widening black/white difference could lead to better prevention strategies.