Overproduction of human Myt1 kinase induces a G2 cell cycle delay by interfering with the intracellular trafficking of Cdc2-cyclin B1 complexes.

The Myt1 protein kinase functions to negatively regulate Cdc2-cyclin B complexes by phosphorylating Cdc2 on threonine 14 and tyrosine 15. Throughout interphase, human Myt1 localizes to the endoplasmic reticulum and Golgi complex, whereas Cdc2-cyclin B1 complexes shuttle between the nucleus and the cytoplasm. Here we report that overproduction of either kinase-active or kinase-inactive forms of Myt1 blocked the nuclear-cytoplasmic shuttling of cyclin B1 and caused cells to delay in the G2 phase of the cell cycle. The COOH-terminal 63 amino acids of Myt1 were identified as a Cdc2-cyclin B1 interaction domain. Myt1 mutants lacking this domain no longer bound cyclin B1 and did not efficiently phosphorylate Cdc2-cyclin B1 complexes in vitro. In addition, cells overproducing mutant forms of Myt1 lacking the interaction domain exhibited normal trafficking of cyclin B1 and unperturbed cell cycle progression. These results suggest that the docking of Cdc2-cyclin B1 complexes to the COOH terminus of Myt1 facilitates the phosphorylation of Cdc2 by Myt1 and that overproduction of Myt1 perturbs cell cycle progression by sequestering Cdc2-cyclin B1 complexes in the cytoplasm.

12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression).

OBJECTIVE: Inpatients with major depressive illness often have coexistent nonaffective psychiatric and/or medical conditions. The authors' objective is to address the following questions: 1) What is the effect of comorbid illness on the severity of major depression and associated psychosocial factors? 2) How does the course of depression differ for patients with and without concurrent illness? 3) Do patients with compound depression differ in rate of recovery and time to recovery from patients with pure depression? METHOD: The subjects were 78 patients with a DSM-III diagnosis of major depression who were consecutively admitted to an acute care university-affiliated psychiatric hospital; 37 of these patients had major depression only and 41 had major depression compounded by a coexisting axis I, II, or III condition. The patients were studied while hospitalized and for 12 months after hospital discharge. Instruments used included the Modified Hamilton Rating Scale for Depression, the Global Assessment Scale, and the Social Readjustment Rating Scale. RESULTS: Patients with compound depression reported significantly poorer functioning over the 12-month follow-up period and had lower recovery rates than the patients with pure depression. There were no differences in recovery rates between men and women with compound depression, but significantly more men than women with pure depression recovered. CONCLUSIONS: Compound depression is a common clinical occurrence, the course of illness is more difficult for patients with compound depression than for patients with pure depression, and the recovery rate of patients with compound depression is lower than that of patients with pure depression.

Recovery and major depression: factors associated with twelve-month outcome.

OBJECTIVE: In spite of the prevalence and chronicity of major depression, there is no consensus regarding which clinical and psychosocial variables are associated with recovery. The authors examined the probability of recovery from a major depressive episode 12 months after hospital discharge, the factors most closely associated with recovery, and the patterns of improvement distinguishing patients who recovered from those who did not. METHOD: Seventy-eight inpatients with a DSM-III diagnosis of major depression were assessed at hospitalization and at monthly intervals for 12 months after discharge on a variety of clinical and psychosocial factors. Recovery status at 12-month follow-up was then used as a basis for comparing acute-phase patient characteristics and change in symptoms over time. RESULTS: By the 12th month of follow-up, 34 (48.6%) of 70 patients met criteria for recovery. The five most important factors related to recovery were shorter length of hospital stay, older age at onset of depression, better family functioning, fewer than two previous hospitalizations, and absence of comorbid illness. The majority of patients who had recovered by 12 months had done so within 6 months of discharge; the average length of time to recovery was 4.9 months. CONCLUSIONS: Patients hospitalized for major depression have less than a 50-50 chance of recovering by 1 year. Some variables associated with nonrecovery (e.g., comorbid illness, poor family functioning) are amenable to clinical intervention; however, findings also suggest that there may be two distinct types of depressive illness with respect to recovery, one that remits quickly and the other with a more prolonged course of illness.

Role of the family in recovery and major depression.

OBJECTIVE: Major depression is significantly influenced by the family environment of the depressed patient. In order to explore how family functioning relates to this illness, the authors examined changes in family functioning over a 1-year course of major depression. METHOD: Subjective (Family Assessment Device) and objective (McMaster Clinical Rating Scale) assessments of family functioning were collected at hospitalization and 6 and 12 months after discharge for 45 inpatients diagnosed with major depression and their family members. Patterns of family functioning were examined by subjective and objective perspectives, initial levels of functioning, and reports of patients and other family members. RESULTS: Approximately 50% of families with a depressed member perceived their own family functioning as unhealthy; clinicians rated 70% of the families as unhealthy. While family functioning improved significantly from hospitalization through 12 months after discharge, the improvement was not uniform across all areas of functioning. Further, patients with good family functioning at hospitalization generally maintained their healthy functioning and were more likely to recover by 12 months than patients with poor family functioning. Although steady improvement in family functioning characterized the subjective ratings, objective assessments of family functioning suggested initial improvement followed by a decline from month 6 to month 12. CONCLUSIONS: Results show a clear association between family functioning and recovery from major depression. Different aspects of family life respond differently to the depressive illness; no one family dimension was uniquely related to outcome.

A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder.

BACKGROUND: This pilot study compared the efficacy of lithium plus divalproex sodium with the efficacy of lithium alone for the continuation and maintenance treatment of patients with bipolar I disorder. METHOD: Twelve patients with bipolar I disorder as defined by the DSM-III-R were recruited and followed prospectively for up to 1 year. Each subject received lithium at serum levels of 0.8 to 1.0 mmol/L and a management/education session weekly or every 2 weeks. By random assignment, subjects received either divalproex sodium or placebo in conjunction with lithium. Divalproex sodium was adjusted to achieve a serum concentration of 50 to 125 micrograms/mL. Adjunctive medications were used on an as needed basis to treat psychosis, depression, and anxiety. The course of illness was monitored through use of the Longitudinal Interval Follow-up Examination. RESULTS: Subjects treated with the combination of lithium and divalproex were significantly less likely to suffer a relapse or recurrence (p = .014), but were significantly more likely to suffer at least one moderate or severe adverse side effect (p = .041). There was no significant difference between groups in the use of adjunctive medication. CONCLUSION: These results provide preliminary evidence of the risks and benefits of combining lithium with divalproex sodium for the continuation and maintenance treatment of bipolar I disorder.

Personality and family functioning in families of depressed patients.

In this cross-sectional study, the authors attempted to identify correlates of family functioning in 86 couples with a depressed member during the acute phase of the patient's depression. Demographic variables, psychiatric status, and personality traits of both the patient and spouse were investigated as potential predictors of family functioning. Regression analyses indicated that lower levels of personality pathology in the patient, higher levels of patient conscientiousness, and less psychological distress in the spouse were associated with healthier family functioning. Future research implications and clinical importance of these findings are discussed.

Depressed patients with dysfunctional families: description and course of illness.

Sixty-eight depressed patients were subdivided according to their family's level of family functioning into functional and dysfunctional groups. Patients from dysfunctional families did not differ from those from functional families on measures of severity of depression, chronicity of depression, depression subtypes, other nonaffective psychiatric diagnoses, history of depression, or neuroendocrine functioning. Patients from dysfunctional families did have significantly higher levels of neuroticism. A 12-month follow-up of these patients indicated that depressed patients with dysfunctional families had a significantly poorer course of illness, as manifested by higher levels of depression, lower levels of overall adjustment, and a lower proportion of recovered patients. Thus, impaired family functioning appears to be an important prognostic factor in major depression.

Psychosocial factors and the long-term course of major depression.

Fifty-nine subjects participated in a telephone follow-up interview 6 years after being hospitalized with a severe major depressive episode and 5 years after completing a 12 month follow-up study. Patient information was used to provide a rating of symptom-free (n = 19), episodic (n = 30), or chronic (n = 10) that described each patient's long-term course of illness. Few variables from the acute stage were related to long-term course of illness; however, early patterns of global and family functioning, number of life events, and rapid reduction in depressive symptomatology were found to be of prognostic significance. For patients whose depression is severe enough to warrant hospitalization, the pattern of functioning in the first few months after discharge from hospital is a strong indicator of the future long-term course.

Gender differences in chronic major and double depression.

BACKGROUND: While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS: 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS: Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS: Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS: Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Age and the dexamethasone suppression test: results from a broad unselected patient population.

We examined the relationship between age and postdexamethasone serum cortisol concentration in 676 psychiatric inpatients with a variety of DSM-III diagnoses. Regardless of diagnosis, patients 65 years and older had significantly higher nonsuppression rates than those below age 65 (64% vs. 34%). The correlation between age and cortisol level was moderate, but significant. Aging is associated with increasing nonsuppression rates to dexamethasone, and this change is augmented by an affective disorder diagnosis. Levels of nonsuppression and age-cortisol correlations vary depending on dose of dexamethasone, diagnosis, and gender.

Right turns only: an evaluation of a video-based, multicultural drug education series for seventh graders.

This study assessed the effectiveness of a video-based, multicultural drug education series for seventh graders. Right Turns Only (RTO) was produced by the Prince George's County Public School System in Maryland and funded by the Center for Substance Abuse Prevention. Knowledge, attitude, and behavioral intentions of 1,036 seventh-grade students who received the RTO curriculum alone or as a supplement to a traditional drug education curriculum (SMART) were measured to test the effects of this video series and its collateral print materials.

Lithium levels and toxicity among hospitalized patients.

OBJECTIVE: Although psychiatrists in the United States have used lithium for nearly 30 years, toxicity still occurs frequently. The authors report an attempt to reduce the incidence of lithium toxicity in hospitalized psychiatric patients and to identify factors associated with toxicity. METHODS: Serum lithium levels were monitored by the drug use evaluation committee at a psychiatric hospital between 1990 and 1996. Each laboratory result showing a serum lithium level of 1.5 mmol/L or more was promptly investigated, and the results were reported quarterly to the hospital staff association. RESULTS: The study found that in 6.8 percent of the 2,210 admissions during which lithium was administered, patients had serum levels of 1.5 mmol/L or higher. The number of excessive serum lithium levels decreased over the course of the study period. Only 27.8 percent of patients with excessive levels had signs and symptoms of toxicity. Of the excessive serum lithium levels that were investigated, 43.3 percent were detected in blood samples drawn at the time of admission. Women and elderly persons were significantly more likely to have excessive serum levels. Psychiatric diagnosis was not significantly associated with excessive serum levels. CONCLUSIONS: Education by the drug use evaluation committee may have helped to reduce the number of patients who experienced excessive lithium levels while hospitalized. Vigilance should be emphasized for women and elderly persons.

Childhood abuse and recovery from major depression.

Thirty-eight female inpatients with major depression were assessed for childhood abuse. History of abuse was examined in relation to recovery from a major depressive episode over a 12-month follow-up period. Forty-six percent of the women had a history of childhood abuse. Women without a history of abuse were 3.7 times more likely to have recovered by 12 months.

Family functioning, social adjustment, and recurrence of suicidality.

We examined suicidal and nonsuicidal patients with major depression during and subsequent to their hospitalization. Factors associated with suicidality at the index episode included psychosocial variables as well as measures of family functioning. Previous suicidality, inter-episodic adjustment, changes in family constellation, and perception of family functioning were instrumental in separating nonsuicidal patients at follow-up from patients exhibiting recurrent suicidal behavior. These results indicate that when assessing patients with major depression for suicidality, particular attention should be paid both to the social environment and to family functioning as perceived by the patient.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures.

OBJECTIVE: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. RESULTS: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. CONCLUSIONS: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. LEVEL OF EVIDENCE: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.

HLA-G is expressed by the glandular epithelium of peritoneal endometriosis but not in eutopic endometrium.

BACKGROUND: HLA-G is a major histocompatability antigen with documented immune-regulatory function. Various epithelial cancers and tissue allografts have been noted to express HLA-G, which is postulated to aid in their escape from immunosurveillance. We evaluated peritoneal endometriosis and eutopic endometrium for the expression of HLA-G protein and gene transcript. METHODS: Two experiments were performed: (i) archived tissue blocks from peritoneal endometriotic lesions (n = 15) and eutopic endometrium (n = 12) were evaluated for extent of protein immunostaining, and (ii) eutopic endometrial biopsies from women without (n = 17) and with (n = 24) endometriosis, and peritoneal endometriotic lesions (n = 14) were evaluated for presence of RNA transcript by in situ hybridization. RESULTS: HLA-G protein localized in the glandular epithelium of 14 of 15 (93.3%) peritoneal endometriotic lesions, but not in stromal cells. HLA-G protein staining was absent in endometrial biopsies (n = 12). HLA-G gene transcript localized to the glandular epithelium in 13 of 14 (92.8%) peritoneal endometriotic lesions. HLA-G transcript was never observed in eutopic endometrium, regardless of cycle stage or whether from women with (n = 24) or without (n = 18) endometriosis. CONCLUSIONS: HLA-G is expressed by endometriotic glandular epithelium but not by eutopic endometrium under normal conditions. Differential expression of HLA-G suggests that peritoneal inflammation or cellular stress may up-regulate mechanisms to promote ectopic endometrial survival.

14-3-3 binding regulates catalytic activity of human Wee1 kinase.

The mitotic inducer Cdc2 is negatively regulated, in part, by phosphorylation on tyrosine 15. Human Wee1 is a tyrosine-specific protein kinase that phosphorylates Cdc2 on tyrosine 15. Human Wee1 is subject to multiple levels of regulation including reversible phosphorylation, proteolysis, and protein-protein interactions. Here we have investigated the contributions made by 14-3-3 binding to human Wee1 regulation and function. We report that the interactions of 14-3-3 proteins with human Wee1 are reduced during mitosis and are stable in the presence of the protein kinase inhibitor UCN-01. A mutant of Wee1 that is incapable of binding to 14-3-3 proteins has lower enzymatic activity, and this likely accounts for its reduced potency relative to wild-type Wee1 in inducing a G(2) cell cycle delay when overproduced in vivo. These findings indicate that 14-3-3 proteins function as positive regulators of the human Wee1 protein kinase.

Polypharmacy in bipolar I disorder.

There are currently three mood stabilizers available for the maintenance treatment of patients with bipolar I disorder: lithium, valproate, and carbamazepine. Unfortunately, monotherapy with each of these conventional agents often fails. To improve outcome, clinicians utilize polypharmacy. Although the efficacy of this practice is largely unknown, because of the lack of controlled studies, data from the United States and Europe indicate polypharmacy is the rule rather than the exception. The few controlled trials that have been conducted indicate that (1) the specific combination of lithium plus imipramine provides no advantage over lithium monotherapy (notwithstanding the inadequacy of lithium monotherapy); (2) the specific combination of lithium and the depot neuroleptic flupenthixol provides no advantage over lithium monotherapy; and (3) the combination of lithium plus carbamazepine may be as effective as lithium plus haloperidol for acute and continuation treatment. Most of the literature on polypharmacy consists of case reports, retrospective chart reviews, and open-label prospective studies, and describes the use of numerous combinations of medications, including lithium plus valproate, lithium plus carbamazepine, and valproate plus carbamazepine. Preliminary findings suggest these combinations may be effective, and that clozapine and high-dose levothyroxine may each be useful as well when combined with other drugs. Further research is necessary to formally evaluate whether these drug combinations are more effective than monotherapy. Until such studies are completed, certain general principles regarding side effects, pharmacodynamics, and pharmacokinetics should be kept in mind when prescribing two or more medications concurrently.

Lithium plus valproate as maintenance polypharmacy for patients with bipolar I disorder: a review.

Standard pharmacotherapy for the maintenance treatment of patients with bipolar I disorder consists of lithium, valproate, or carbamazepine. However, many patients fail to respond to monotherapy with any of these agents, and as a result, psychiatrists often resort to polypharmacy. Findings from some open-label trials and retrospective chart reviews suggest this approach may be useful, but in the few controlled trials that have been conducted, the results have been negative. One drug combination that warrants further study as maintenance therapy is lithium plus valproate. Each is approved by the U.S. Food and Drug Administration for treatment of acute mania, and lithium has demonstrated efficacy for maintenance treatment as well. Some preliminary evidence suggests that the combination can be effective for patients who do not respond to monotherapy, and it seems to be no more dangerous than monotherapy. Concomitant administration of lithium plus valproate does not significantly alter lithium pharmacokinetics, and statistically significant changes that arise in valproate pharmacokinetics are not clinically significant. Although it is not known whether the drugs interact to augment response, many of their effects in the central nervous system do differ, and there is no indication of pharmacodynamic interactions that oppose each other. Finally, some evidence suggests that lithium and valproate may differ with regard to clinical variables that predict response to treatment.

Family functioning and suicidality in depressed adults.

This study examined the association between suicidality, family factors, and clinical and diagnostic variables in depressed adult inpatients. The subjects were 121 depressed adult inpatients living with a family member or significant other. Demographic, clinical, and diagnostic information about the patient, and subjective and observer ratings of family functioning were obtained. Trained interviewers rated families of suicidal depressed patients as more dysfunctional than families of patients with no history of attempted suicide. In a logistic regression model, earlier age of depression onset, number of psychiatric hospitalizations, and objectively rated poorer family communication were associated with a history of a prior suicide attempt. Also, modest evidence suggested that patients with a prior suicide attempt perceived their families as more dysfunctional than did their respective family members. Variations in family functioning are associated with different degrees of suicidality. However, prospective longitudinal designs would elucidate the causal relation between family dysfunction and suicidal behavior.