Prevention of Depression in At-Risk Adolescents: Moderators of Long-term Response.

In a randomized controlled trial, we found that a cognitive behavioral program (CBP) was significantly more effective than usual care (UC) in preventing the onset of depressive episodes, although not everyone benefitted from the CBP intervention. The present paper explored this heterogeneity of response. Participants were 316 adolescents (M age = 14.8, SD = 1.4) at risk for depression due to having had a prior depressive episode or having current subsyndromal depressive symptoms and having a parent with a history of depression. Using a recursive partitioning approach to baseline characteristics, we (Weersing et al. 2016) previously had identified distinct risk clusters within conditions that predicted depressive episodes through the end of the continuation phase (month 9). The present study used the same risk clusters that had been derived in the CBP group through month 9 to reclassify the UC group and then to examine group differences in depression through month 33. We found that in this overall very high-risk sample, the CBP program was superior to UC among youth in the low-risk cluster (n = 33), characterized by higher functioning, lower anxiety, and parents not depressed at baseline, but not in the middle (n = 95) and high-risk (n = 25) clusters. Across conditions, significantly more depression-free days were found for youth in the low-risk cluster (M = 951.9, SD = 138.8) as compared to youth in the high-risk cluster (M = 800.5, SD = 226.7). Identification of moderators, based on purely prognostic indices, allows for more efficient use of resources and suggests possible prevention targets so as to increase the power of the intervention.

Antisperm antibodies and conception.

Sperm have been known to be antigenic for more than a century. There is a strong body of evidence that in humans and in other species at least some antibodies that bind to sperm antigens can cause infertility. Therefore, these antibodies are of interest today for two practical reasons. Firstly, the association of the antibodies with infertility means that they must be detected and then the couples treated appropriately. Secondly, because these antibodies can induce infertility they have the potential to be developed for contraceptive purposes in humans and also for the control of feral animal populations.

Hyperactivation of capacitated human sperm correlates with the zona pellucida-induced acrosome reaction of zona pellucida-bound sperm.

BACKGROUND: The aim of this study was to determine the relationship between human sperm hyperactivation (HA), sperm-zona pellucida (ZP) binding and the ZP-induced acrosome reaction (AR) of ZP-bound sperm in vitro. METHODS: Sperm samples from 129 infertile men were studied. Motile sperm (2 x 10(6)) selected by Pure sperm were incubated with four oocytes in 1 ml human tubal fluid supplemented with 10% human serum. After 2-h incubation, the number of sperm bound to the ZP and the AR of ZP-bound sperm were examined. Velocities and HA of sperm in insemination medium were assessed by Hamilton-Thorn Sperm Analyzer. RESULTS: The HA was highly correlated with the ZP-induced AR in all the subjects (rho = 0.626, P < 0.001). In the 69 men with < or = 100 sperm bound/ZP, allowing accurate counts, HA was not significantly correlated with sperm-ZP binding. Men with <7% HA sperm were more likely to have very low ZP-induced AR. Only normal sperm morphology was significantly correlated with sperm-ZP binding (rho = 0.346 and 0.446 in semen and insemination medium, respectively, both P < 0.001). Sperm motility and velocities were significantly correlated with sperm morphology but not with either sperm-ZP binding or the ZP-induced AR. CONCLUSIONS: The correlation of HA with the ZP-induced AR of ZP-bound sperm suggests a mechanistic link between HA and the physiological AR in humans. Assessment of HA of capacitated sperm in vitro may be a useful clinical test for male infertility associated with defective ZP-induced AR that does not require the use of human oocytes.

Tyrosine phosphorylation on capacitated human sperm tail detected by immunofluorescence correlates strongly with sperm-zona pellucida (ZP) binding but not with the ZP-induced acrosome reaction.

BACKGROUND: Protein tyrosine phosphorylation (TP) of human sperm is related to sperm capacitation and zona pellucida (ZP) binding. The aim of this study was to determine whether the TP of capacitated sperm is a useful marker for the ability of sperm to bind to the ZP and undergo the ZP-induced acrosome reaction (AR). METHODS: Semen samples were obtained from 115 subfertile men with sperm count > or =20 x 10(6)/ml, motility > or =25% and variable morphology. Motile sperm (2 x 10(6)/ml) selected by swim-up were incubated with four oocytes for 2 h, and the number of sperm bound to the ZP and the ZP-induced AR was examined. TP of sperm tail was assessed by immunofluorescence (IF) with anti-phosphotyrosine monoclonal antibody. The time course and effects of dibutyryl cyclic adenosine monophosphate (dbcAMP) and phorbol myristate acetate (PMA) on TP were also studied. RESULTS: TP was stimulated more by dbcAMP (P < 0.001) and less by PMA (P < 0.05). TP increased significantly with time of incubation of sperm. TP was not detectable on the surface of unfixed live sperm by either Dynabeads or IF. Sperm TP at 2, 4 and 20 h incubation was all significantly correlated with sperm-ZP binding but not with the ZP-induced AR. CONCLUSION: Sperm TP detected by IF correlates strongly with sperm-ZP binding capacity but not with the ZP-induced AR. This simple IF assay of TP may be a clinically useful test of sperm function that is predictive of normal sperm ZP-binding capacity.

Hyper-osmotic condition enhances protein tyrosine phosphorylation and zona pellucida binding capacity of human sperm.

BACKGROUND: The aim of this study was to determine the effect of culture medium osmolality, in the range known to occur in the male and female reproductive tracts, on human sperm tyrosine phosphorylation and sperm-zona pellucida (ZP) interaction in vitro. METHODS: Motile sperm (2x10(6)), selected by swim-up from semen of normozoospermic men with normal sperm-ZP binding, were incubated with or without four oocytes in 1 ml human tubal fluid (HTF) medium with different osmolalities (150, 200, 280, 350, 400 mOsm/kg) adjusted by variation of the NaCl concentration. After 2 h incubation, the number of sperm bound to the four ZP was examined, sperm motility and velocities were assessed by Hamilton-Thorn Motility Analyzer (IVOS 10) and sperm tyrosine phosphorylation was assessed by both western immunoblotting and immunofluorescence with an anti-phosphotyrosine monoclonal antibody (PY20). The effect of hyper-osmolality (400 mOsm/kg) on the ZP-induced acrosome reaction (AR) was also determined. RESULTS: Incubation of human sperm in hyper-osmotic medium significantly increased tyrosine phosphorylation and the number of sperm bound to the ZP. In contrast, hypo-osmotic medium significantly decreased both tyrosine phosphorylation and sperm-ZP binding. Medium with high osmolality (400 mOsm/kg) significantly reduced the ZP-induced AR. Both hypo- and hyper-osmotic media significantly decreased average sperm percentage progressive motility and velocities. CONCLUSION: Incubation of human sperm in hyper-osmotic media was associated with significantly increased tyrosine phosphorylation and ZP-binding ability but severely reduced the ZP-induced AR.

Exposure of actin on the surface of the human sperm head during in vitro culture relates to sperm morphology, capacitation and zona binding.

BACKGROUND: The aim of this study was to determine the relationship between the proportion of motile sperm with actin exposed on the surface of the head and sperm function. METHODS: Semen samples were obtained from normozoospermic men and sperm function tests were performed. Motile sperm selected by swim-up were incubated with actin monoclonal antibody (A-mAb, 1:100) for 2 h, then anti-mouse IgG Dynabeads were used to detect sperm-bound A-mAb. Sperm capacitation was increased by phorbol myristate acetate (PMA) and decreased by bicarbonate-free medium. RESULTS: The proportion of sperm with exposed actin increased with time for up to 2 h incubation. Bicarbonate-free medium significantly decreased the proportion of sperm with exposed actin. PMA significantly enhanced this phenomenon. Sperm bound to zona pellucida (ZP) had a significantly higher proportion with exposed actin than did sperm remaining in medium. Of the 79 samples studied, an average of 9.4% (range 1-27%) of motile sperm had exposed actin after 2 h incubation and this was significantly correlated with sperm normal morphology and ZP binding. CONCLUSION: Exposure of actin on the surface of the sperm head during in vitro culture may be related to membrane modification during sperm capacitation and hence may be a useful marker for this subpopulation of sperm.

Automated semen analysis: 'zona pellucida preferred' sperm morphometry and straight-line velocity are related to pregnancy rate in subfertile couples.

BACKGROUND: Standard semen analysis has low objectivity and reproducibility and is not closely related to fertility. We assess the prognostic value of automated measurements of sperm motility and morphology. METHODS: During 1997-1999, 1191 infertile couples with no known absolute barrier to conception were assessed by conventional semen analysis, and automated measurements of average straight-line velocity (VSL) and the percentage of sperm with characteristics that conform to those of sperm which bind to the zona pellucida of the human oocyte (%Z). During follow-up to 2001, there were 336 natural pregnancies. RESULTS: Only %Z, VSL and female age were independently significantly related to pregnancy rate by Cox regression analysis. Pregnancy rate was higher with above average %Z and VSL, indicating a continuous rather than a threshold relationship. The likelihood of pregnancy within 12 cycles can be evaluated for specific values of %Z, VSL and female age using the Cox regression model. CONCLUSIONS: The automated semen measures of sperm morphometry (%Z) and velocity (VSL) are related to pregnancy rates in subfertile couples and should assist clinicians in counselling subfertile patients about their prognosis for a natural pregnancy. Objective automated methods should replace the traditional manual assessments of semen quality.

Improved sperm cryopreservation using cold cryoprotectant.

It has generally been assumed that very rapid cooling above freezing point would be deleterious to human sperm because it would result in cold shock. Consequently, most routine cryopreservation protocols involve the use of warm (20-30 degrees C) cryoprotectant and slow cooling above the freezing point in order to minimise the risk of cold shock. In order to test this assumption, we added an equal volume of cold (4 degrees C) cryoprotectant in a single aliquot to warm (20, 30 or 37 degrees C) semen to induce rapid cooling. The results of this procedure were compared with those obtained using warm cryoprotectant or with the routine cryopreservation protocol used in this laboratory. The use of cold cryoprotectant resulted in a significant (P = 0.016) improvement (mean 63%, range 42%-79%) in post-thaw motility recovery compared with a standard procedure(mean 47%, range 35%-67%) and a significant (P = 0.016) improvement in post-thaw sperm velocity. A cold glycerol/egg yolk/citrate (GEYC) mixture also gave significantly higher motility recovery than GEYC equilibrated to either room temperature (20 degrees C) or body temperature (37 degrees C). Sperm frozen using the cold cryoprotectant protocol were as efficient at binding to and penetrating the human zona pellucida as sperm frozen with a standard protocol. The modified cryopreservation procedure may lead to improved pregnancy rates in donor insemination and in vitro fertilisation. Further investigation is required to determine how the cold cryoprotectant improves the cryopreservation outcome.

An anti-actin monoclonal antibody inhibits the zona pellucida-induced acrosome reaction and hyperactivated motility of human sperm.

We report an inhibitory effect of an anti-actin monoclonal antibody (mAb) on the human zona pellucida (ZP)-induced acrosome reaction (AR). Motile sperm were incubated with native human ZP for 2 h in medium containing either the anti-actin mAb, an irrelevant control mAb or cytochalasins B or D (40 micromol/l). Sperm bound to the ZP were recovered and the AR was determined by fluorescein-labelled Pisum Sativum agglutinin. Anti-mouse immunoglobulin G (mIgG) Dynabeads, immunofluorescence and immunogold were used to detect the location of the anti-actin mAb in sperm. The anti-actin mAb significantly inhibited the ZP-induced AR (equivalent to cytochalasins), the ionophore A23187-induced AR and hyperactivation of sperm in medium. After incubation with anti-actin mAb, anti-mIgG beads bound to the head of >50% of sperm recovered after binding to the ZP and 10% of sperm remaining in the medium. The proportion of sperm that bound anti-mIgG beads after recovery from binding to the ZP in the presence of the anti-actin mAb was significantly correlated with the ZP-induced AR in the absence of the antibody. Immunofluorescence and immunogold demonstrated entry of the anti-actin mAb into sperm. This study suggests that the sperm plasma membrane becomes permeable to the anti-actin mAb during capacitation and initiation of the AR.

A randomized trial of a group cognitive intervention for preventing depression in adolescent offspring of depressed parents.

BACKGROUND: Adolescent offspring of depressed parents are at high risk for development of depression. Cognitive restructuring therapy holds promise for preventing progression to depressive episodes. METHODS: A randomized, controlled trial was conducted to prevent depressive episodes in at-risk offspring (aged 13-18 years) of adults treated for depression in a health maintenance organization (HMO). Potential adult cases were found by reviewing the HMO pharmacy records for dispensation of antidepressant medication and the mental health appointment system. Medical charts were reviewed for a depression diagnosis. Recruitment letters signed by treating physicians were mailed to adults. Eligible offspring had subdiagnostic depressive symptoms insufficient to meet full DSM-III-R criteria for affective disorder and/or a past mood disorder. These youth were randomized to usual HMO care (n = 49) or usual care plus a 15-session group cognitive therapy prevention program (n = 45). RESULTS: We detected significant treatment-by-time (program) effects for the Center for Epidemiological Studies Depression Scale (P=.005) and the Global Assessment of Functioning scores (P =.04). Survival analysis of incident major depressive episodes during a median 15-month follow-up found a significant advantage (P =.003) for the experimental condition (9.3% cumulative major depression incidence) compared with the usual-care control condition (28.8%). CONCLUSION: A brief, group cognitive therapy prevention program can reduce the risk for depression in the adolescent offspring of parents with a history of depression.

Screening for anxiety and depression in early adolescence.

OBJECTIVE: To examine the level of diagnostic and discriminative accuracy of three dimensional rating scales for detecting anxiety and depressive disorders in a school-based survey of 9th grade youths. METHOD: Classroom screening instruments, the Center for Epidemiologic Studies-Depression Scale (CES-D), the Revised Children's Manifest Anxiety Scale (RCMAS), and the Multidimensional Anxiety Scale for Children (MASC) were administered to 632 youths from three sites in 1998. On the basis of rating scale results, samples of high-scoring and non-high-scoring youths were invited to participate in a diagnostic interview conducted within 2 months of the screening sessions. RESULTS: MASC scores were most strongly associated with individual anxiety disorders, particularly among females, whereas the CES-D composite score was associated with a diagnosis of major depression, after controlling for comorbid disorders. The RCMAS was least successful in discriminating anxiety and depression. When receiver operator characteristic curves were examined, diagnostic accuracy was moderate. CONCLUSIONS: The ability of the MASC and CES-D to discriminate within and between categorically defined diagnostic groups has important implications for the accurate identification of youths in need of services.

Mediating mechanisms in a program to reduce intentions to use anabolic steroids and improve exercise self-efficacy and dietary behavior.

This study investigated the mediating mechanisms responsible for the effects of a program designed to reduce intentions to use anabolic steroids, improve nutrition, and increase strength training self-efficacy. Fifteen of 31 high school football teams (N = 1,506 players at baseline) in Oregon and Washington were assigned to receive the intervention. The multicomponent program addressed the social influences promoting ergogenic drug use and engaging students in healthy nutrition and strength training alternative behaviors. Although the results differed across the three dependent variables, the program appeared to work by changing team norms. Unlike prevention of other drugs, changes in knowledge and perceived severity were mediators of program effects in this study.

Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

Impact of comorbidity on a cognitive-behavioral group treatment for adolescent depression.

OBJECTIVE: Examine hypotheses concerning the negative impact of lifetime psychiatric comorbidity on participation in, and benefit from, a cognitive-behavioral group treatment for depression in adolescents (e.g., greater severity at intake, less recovery and more recurrence, less participation in treatment). METHOD: Across two previous studies conducted between 1986 and 1993, 151 depressed adolescents (aged 14-18) were randomly assigned to one of three treatment conditions (two active treatments and a waitlist control) and followed for 24 months posttreatment. Forty percent of participants had one or more lifetime comorbid diagnoses at intake. RESULTS: Comorbid anxiety disorders were associated with higher depression measure scores at intake and greater decrease in depression scores by posttreatment. Overall lifetime comorbidity was unrelated to diagnostic recovery, but lifetime substance abuse/dependence was associated with slower time to recovery. Participants with attention-deficit and disruptive behavior disorders were more likely to experience depression recurrence posttreatment. Associations between comorbidity and participation or therapy process measures were nonsignificant. CONCLUSIONS: Although some outcomes were worse for some comorbid diagnoses, the reassuring overall conclusion is that the presence of psychiatric comorbidity is generally not a contraindication for the use of structured group cognitive-behavioral interventions for depressed adolescents.

Frequency of disordered zona pellucida (ZP)-induced acrosome reaction in infertile men with normal semen analysis and normal spermatozoa-ZP binding.

Results of zona pellucida (ZP)-induced acrosome reaction (AR) are reported for 186 normospermic men with unexplained infertility and compared with 34 normal fertile men and 54 patients with disordered ZP-induced AR (DZPIAR) diagnosed after failure of standard IVF. For each ZP-induced AR test, four oocytes that failed to fertilize in IVF were incubated for 2 h with 2x10(6)/ml motile spermatozoa. Spermatozoa tightly bound to the ZP were recovered by aspirating the oocytes with a pipette and the AR assessed using pisum sativum agglutinin labelled with fluorescein. The standard deviation of the difference was 5.2% for repeated tests for ZP-induced AR on different ejaculates from 54 men. The ranges for the ZP-induced AR were 3-98% for normospermic infertile men, 24-95% for fertile men and 0-16% for DZPIAR patients. In the normospermic group, there was a significant correlation between ZP-induced AR and sperm concentration (Spearman r = 0.238, P < 0.001). Using ZP-induced AR < or =16% as the threshold for diagnosis of DZPIAR, the frequency of this condition in normospermic infertile men would be 25%. Thus DZPIAR is common with normospermic idiopathic infertility and this condition should be diagnosed before assisted reproductive technology since it requires intracytoplasmic sperm injection.

Effectiveness of antidepressant pharmacotherapy: the impact of medication compliance and patient education.

This study was designed to investigate the impact of a time-phased patient education program (RHYTHMS) on medication compliance and treatment outcomes of primary care patients diagnosed with major depression and started on antidepressant pharmacotherapy. Two hundred forty-six depressed patients, diagnosed and treated at one of three outpatient clinics affiliated with the Kaiser-Permanente Northwest Region (KPNW) healthcare system, were randomly assigned to either receive or not receive (usual care) the educational materials by mail. Depression severity and functional impairment affecting patients' quality of life were assessed at baseline and 4, 12, and 30 weeks later. Self-reported impressions of improvement and patient satisfaction with treatment were also assessed at follow-up. Clinical assessment data were obtained using an interactive voice response (IVR) system. Study subjects were compensated $5, $10, $15, and $25 for completing each assessment (Baseline to Week 30, respectively). Upon study completion, prescription fill data of the subjects were extracted from the KPNW Pharmacy System for analysis of medication compliance. Most of the study subjects (63.5%) responded to the pharmacotherapy treatment by study end-point. Few statistically significant differences in either treatment outcomes or duration of medication compliance were found between the treatment groups, and significant differences found were of fairly small magnitude. Patients not receiving the educational materials initially exhibited a more positive response to treatment (Week 4), but this difference did not persist at later follow-ups and was associated with significantly higher relapse rates. A strong time-dose relationship was evident between the duration of the initial treatment episode and treatment outcomes at follow-up, but randomized treatment assignment did not influence the duration of initial medication compliance. Educational programs designed to encourage depressed patients to obtain adequate pharmacotherapy likely provide medical benefits. Such benefits appear to be relatively subtle and methodological differences between studies contribute to inconsistent conclusions concerning observed benefits. The intent of providing time-phased educational materials to patients is to maximize the relevance of such information by synchronizing it with typical recovery processes and issues. This study suggests that additional efforts at engaging patients earlier after the initiation of treatment might be of most benefit.

Treated prevalence, incidence, and pharmacotherapy of child and adolescent mood disorders in an HMO.

This study examined the "treated" prevalence, incidence, and pharmacotherapy of child and adolescent mood disorders in a managed care setting. General prevalence patterns across age and sex were similar to those reported in community epidemiology studies, although, not unexpectedly, the overall rates were somewhat lower. Primary care providers identified a substantial proportion of the youth with a mood disorder. Antidepressant medication was used more often by youth identified with a mood disorder in medical care settings than by those youth identified in specialty mental health care settings. These results are valuable in determining if youth with mood disorders receiving medication prescriptions across settings are treated according to current best practice guidelines (such as the adult depression guidelines [U.S. Department of Health and Human Services, 1993]), that is, primarily with SSRI medications.

Feasibility of surveillance of changes in human fertility and semen quality.

To show that male fertility is declining is not simple. Few men volunteer and recruitment bias may lead to over-representation of the subfertile. Semen analysis has errors arising from counting and poorly standardized criteria, which may be overcome by automation. Time to pregnancy (TTP)-the number of menstrual cycles taken to conceive-measures fertility and allows male recruitment bias to be estimated. We review automated measurement of sperm concentration, motility and morphology and present a preliminary report on a study to assess a retrospective TTP questionnaire, recruitment bias and feasibility for large-scale surveillance of fertility.

Psychiatric hospitalizations, arrests, emergency room visits, and homelessness of clients with serious and persistent mental illness: findings from a randomized trial of two ACT programs vs. usual care.

OBJECTIVE: This investigation examined several adverse outcomes in clients with serious mental illness in a randomized trial of Assertive Community Treatment (ACT) versus usual care. METHOD: 163 subjects were randomized to one of two ACT experimental conditions (staffed by consumers or non-consumers) or usual community care. Conditions were compared on psychiatric hospitalization, emergency room visit, arrest, and homelessness, within the two-year study period. Demographic, program, and client variables were examined for significant associations with outcomes. RESULTS: Significant differences were found between ACT and usual care in time to first arrest, but not hospitalization, homelessness or ER visits. Shorter time to first hospitalization was associated with male gender, diagnoses other than schizophrenia, high psychiatric symptomatology and lower provider case load. ER visits were associated with increased client symptomatology. Shorter times to homelessness were predicted by poorer therapeutic alliance between case manager and clients. Shorter time to first arrest was predicted by client minority status and enrollment in usual care. CONCLUSIONS: The paucity of significant main effects may have been due to a prolonged "start-up" phase of the ACT programs, poor ACT implementation, restricted availability of psychiatric hospital beds, or changes in usual care services delivered over the study period.