A protocol for the pharmacologic treatment of major depression. A field test of a potential prototype.

BACKGROUND: Much attention is being given to developing clinical practice guidelines for management of mental health disorders. The aim of this study was to field test a prototype protocol for the pharmacologic treatment of Major Depression. METHOD: The protocol consisted of four, six week, treatment phases with critical choices in therapy defined by scores on the MADRS (Montgomery Asberg Depression Rating Scale). Observational data as collected on the behaviour of the protocol in terms of relevance, acceptability, ease of use and effectiveness. RESULTS: Effectiveness of the protocol was good for those patients who were retained within it, with three quarters of them attaining remission. However more than half of all patients dropped out-non attendance and adverse events being the most common reasons for this. CONCLUSION: The protocol for the treatment of Major Depression appeared relevant, easy to use and potentially effective. LIMITATION: Problems with non-adherence by both doctors and patients posed major challenges to the protocol's design. Such difficulties demonstrate the need to field test any proposed design as preconceptions about a protocol's performance may be misplaced. CLINICAL RELEVANCE: The protocol tested represents progress towards the goal of developing optimal strategies for the use of pharmacotherapeutic agents in the treatment of depression.

Safety and tolerability of combined treatment with moclobemide and SSRIs: a systematic study of 50 patients.

Fifty major depressed patients, resistant to multiple pharmacotherapies, were treated by the addition of moclobemide (up to 600 mg/day) to paroxetine or fluoxetine (20 mg/day) for 6 weeks in an open study to assess tolerability. There were 188 adverse events: insomnia, dizziness, headache, nausea, dry mouth and myoclonic jerks were the most common. Many events were rated as severe. The high rate of adverse events suggest that there are clinically significant pharmacodynamic interactions between moclobemide and SSRIs. However the uncontrolled data on effectiveness is encouraging and the combination deserves further consideration as a strategy for treating intractable depression.

Outcome study using an administrative database: terminal salpingostomy, physician case load and live birth rates.

Information on the outcome following salpingostomy performed for infertility in everyday practice is needed to counsel patients, determine the best approach to this condition and clarify whether the outcome is superior when surgery is performed by a physician who maintains a high volume of ongoing experience. A total of 547 consecutive subjects were identified over a 5 year period using the Alberta Health Care Claims Database. Their claims history was analysed over a follow-up of 2-7 years, to identify pregnancy-related events, loss to follow-up and events which would result in sterility. Pregnancies were cross-checked with the only in-vitro fertilization programme serving the region. The overall cumulative live birth and tubal pregnancy rates were 11.7 and 7.2% respectively. Live birth rates were significantly higher when practitioners had performed >10 procedures within the study period. Live birth rates would appear to be substantially lower in everyday practice than following surgery performed by acknowledged experts. A high volume of ongoing experience appears to be associated with superior live birth rates. It is unclear whether this association relates to case selection, surgical expertise or both variables.

Safety and tolerability of combined treatment with moclobemide and SSRIs: a preliminary study of 19 patients.

Nineteen major depressed patients, resistant to previous pharmacotherapies, were treated by the addition of moclobemide (up to 600 mg/day) to paroxetine or fluoxetine (20 mg/day) for 6 weeks in an open study to assess the adverse events and tolerability. There were 77 emergent events, insomnia, headache, nausea and dizziness being the most common. Many events were rated as severe. The high rate of adverse events suggests that there may be clinically significant interactions between moclobemide and SSRIs. However, the uncontrolled data on effectiveness is encouraging and the combination deserves further attention as a strategy for treating intractable major depression.

Chromosomal analysis of sperm from men with idiopathic infertility using sperm karyotyping and fluorescence in situ hybridization.

OBJECTIVE: To determine if idiopathic infertile men having oligozoospermia, asthenozoospermia, or teratozoospermia have an elevated risk of transmitting chromosomal abnormalities to their offspring. DESIGN: Sperm chromosomal complements from five somatically normal infertile men were assayed using the human sperm-hamster oocyte fusion system and the disomy frequencies for chromosomes 1, 12, and the sex chromosomes were determined using fluorescence in situ hybridization. SETTING: Infertile men and normal donors were volunteers in an academic research environment. PATIENTS: Five men with the appropriate semen characteristics were recruited among patients concerned about their infertility. INTERVENTIONS: Sperm fused with hamster oocytes resulting in sperm chromosomes or the sperm nuclei were prepared for fluorescence in situ hybridization. MAIN OUTCOME MEASURE: Structural and numerical abnormalities assessed by sperm karyotypes and the disomy frequency determined by fluorescence in situ hybridization analysis. RESULTS: The infertile men showed increased frequencies of numerical abnormalities and total abnormalities as determined by sperm karyotyping. Analysis of sperm nuclei by fluorescence in situ hybridization indicated a significant increase in the frequency of disomy for chromosome 1 and XY disomy. CONCLUSIONS: Sperm from infertile men may contain an increased frequency of chromosomal abnormalities.

Human embryo implantation following in-vitro fertilization: is there a seasonal variation?

The purpose of this study was to determine whether there is a seasonal variation in implantation and pregnancy rates following natural cycle replacement of cryopreserved embryos. A total of 321 consecutive cycles were analysed. There were 59 pregnancies (18.4%) and 48 live births or ongoing pregnancies (15.0%). Indicator variables for each month and variables representing temporal cycles of 12, 6, 4, 3 and 2 months were related to outcome. In addition, an analysis of periodicity was performed. No temporal, clinical or demographic variable was significantly related to pregnancy. This study indicated that there was no clear seasonal variation in the pregnancy rate following natural cycle replacement. However, the power of this study was low, and it was estimated that 963 subjects would be required to detect a 10% seasonal difference in pregnancy rates.

Outcome of thaw embryo transfer after cryopreservation of all embryos in patients at risk of ovarian hyperstimulation syndrome.

OBJECTIVE: To determine the incidence of ovarian hyperstimulation syndrome (OHSS) and subsequent pregnancy rates (PRs) if ET is delayed in patients at risk of OHSS by allocating all embryos to cryopreservation. DESIGN: Retrospective analysis of clinical and laboratory data from 724 consecutive stimulated cycles of IVF. SETTING: University hospital-based IVF program. PATIENTS: Consecutive patients undergoing IVF between September 1989 and December 1992. MAIN OUTCOME MEASURES: Fertilization rates, cryosurvival rates, subsequent PRs, and the occurrence of severe OHSS. RESULTS: Ten of the 564 patients (1.8%) who had ET in the stimulation cycle developed severe OHSS. Sixty-nine patients had all embryos frozen because of the risk of OHSS, of which one (1.4%) developed severe OHSS. The subsequent PR after thaw transfer was 25.2% per transfer, with a cumulative PR per patient after additional thaw transfers of 40.6%. CONCLUSIONS: Cryopreservation of all embryos and delayed ET in patients at risk of OHSS results in a low incidence of severe OHSS. Oocyte quality, fertilization rates, and cryosurvival of frozen embryos are equal to those for patients who have a normal stimulation profile. Subsequent thaw embryo replacements result in a satisfactory PR.

Embolization of the uterine arteries before termination of a 15-week cervical pregnancy.

The authors describe a patient with a 15-week cervical pregnancy after in-vitro fertilization. The pregnancy was safely aborted after preoperative embolization of the uterine arteries. Fertility was preserved.

Cervical pregnancy following in vitro fertilization: evacuation after uterine artery embolization with subsequent successful intrauterine pregnancy.

A case is described in which a cervical pregnancy followed in vitro fertilization. Treatment was delayed at the request of the patient until the second trimester, and was successfully managed by preoperative bilateral angiographic uterine artery occlusion, surgical evacuation, and postoperative balloon tamponade. Subsequent embryo transfer of previously cryopreserved embryos resulted in a normal intrauterine pregnancy and delivery without complications. This case highlights the need for awareness of cervical pregnancy following in vitro fertilization and the success of management which preserves fertility.

Factors predicting outcome in 215 consecutive thawed embryo replacements.

This retrospective study was undertaken to determine which factors were associated with outcome in thawed embryo replacement cycles. The number of embryos replaced and the response to exogenous ovarian stimulation in the original IVF cycle were significantly associated with the conception rate.

Office falloposcopy; a tertiary level assessment for planning the management of infertile women.

Thirty-nine women underwent Falloposcopic examination utilizing the linear eversion catheter. Indications for examination included bilateral and unilateral proximal and distal tubal occlusive disease, assessing the residual Fallopian tube after salpingectomy for ectopic pregnancy, and unexplained infertility. Seventy-three Fallopian tubes were available for examination, of which 72 (98.6%) were successfully cannulated. Sixty-eight ampullas were successfully visualized (94.4%). The mean duration of the examination was 24.7 minutes. Where proximal tubal disease was not suspected, 30.3% of oviducts were found to have a proximal lesion and 57.5% were found to have distal intratubal disease.

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1.

Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome (1)(p31q12). Q-banded pronuclear chromosomes were analyzed after in vitro penetration of golden hamster oocytes. A total of 159 sperm were examined: 54% bearing the inverted chromosome 1 and 46% the normal chromosome 1. These frequencies are not significantly different from the theoretical 1:1 ratio. There were no recombinant sperm with duplications or deficiencies, suggesting that a pairing loop failed to form or that crossing-over was suppressed. The frequency of abnormalities unrelated to the inversion was 5% for numerical, 8.8% for structural, 2.5% for numerical and structural, values not significantly different from control donors studied in our lab. The frequencies of X- and Y-bearing sperm were 46% and 54%, respectively, not significantly different from the expected value of 50%. This is the fifth pericentric inversion studied by human sperm chromosome analysis; recombinant chromosomes have been observed in two of the five cases. Some of the factors associated with an increased risk of recombinant sperm appear to be inversion size greater than 30% of the chromosome and chromosome breakpoints in G-light bands.

Production and characterization of monoclonal antibodies to embryo-associated immunosuppressor factor (EASF) produced by human pre-implantation embryo.

Balb/c mice were immunized with pre-implantation embryo-associated immunosuppressor factor (EASF) (purified from embryo growth media of in vitro fertilized human ova). Hybridoma clones were produced by fusing their spleen cells with NS1 and P3X653 myeloma cell lines. The presence of specific anti-EASF monoclonal antibodies (mAb) in the hybridoma culture supernatants were tested by enzyme-linked immunosorbent assay. A total of 15 hybridoma clones were selected, and their products were purified and characterized. Each mAb bound specifically to its antigen in a dose-dependent manner. The affinity-purified EASF from embryo growth media demonstrated immunosuppressive activity on Concanavalin A-induced lymphocytes and the presence of 14 kDa, 24 kDa and 37 kDa factors. No such activity or similar molecules were identified when control growth media were analyzed. This clearly demonstrates that these mAb are indeed EASF-specific and are able to recognize biologically active immunosuppressive components in embryo growth media. These mAbs are presently being tested for the development of EASF-specific assay system.

Infertility: a non-event transition.

OBJECTIVE: To determine the predictive validity of four transition variables and seven individual variables in differentiating between individual responses to infertility. DESIGN: Forty-three primary infertile women and 28 men attending a general infertility treatment clinic voluntarily agreed to participate in this cross-sectional study and completed five standardized instruments on a one-time-only basis. RESULTS: Adjustment to infertility was related to positive self-esteem, internal locus of control, higher socioeconomic status, and moderate age. High levels of anxiety and distress were related to low self-esteem, undifferentiated sex role identity, and advanced age. Actual and perceived duration of infertility were factors also related to participants' responses to infertility. CONCLUSION: Results highlight the importance of psychological assessment and continuing support in the management and treatment of infertility, with concerns being raised regarding the advisability of protracted medical intervention.

The mouse embryo culture system: improving the sensitivity for use as a quality control assay for human in vitro fertilization.

OBJECTIVE: To determine whether the mouse embryo culture system can be sensitized to provide improved differentiation of suboptimal culture media for in vitro fertilization. DESIGN: Mouse embryo development in media prepared from one of three water sources were compared using embryos from two mouse strains, culturing embryos from either zygote or two-cell stage, and pretreating with either zona removal and/or cryopreservation. SETTING: Academic research department, tertiary care referral center. RESULTS: Embryos from CD1 mice were able to develop in suboptimal culture conditions, even when pretreated with zona removal or cryopreservation. Embryos from B6CBA/F1J mice were more sensitive to suboptimal culture conditions when harvested at the zygote stage than at the two-cell stage, and this sensitivity was improved after zona removal before culture. CONCLUSIONS: The mouse embryo culture system has deficiencies as an assay of culture medium quality, but the sensitivity of the assay can be optimized by harvesting at the zygote stage from an appropriate strain and by zona pellucida removal before culture.

Exogenous control of the cycle simplifies thawed embryo transfer and results in a pregnancy rate similar to that for natural cycles.

To determine if a satisfactory PR could be achieved in thawed ET using a simplified protocol, standard monitoring in the natural cycle was compared with a controlled preparation of the endometrium with exogenous E2 and P without hormonal or ultrasonographic monitoring. All patients had normal ovarian function, and no GnRH-a were administered. Pregnancy rates, ongoing PRs, and embryo implantation rates were similar in the two groups. The use of exogenous E2 and P without GnRH-a suppression to control the cycle for thaw ET is safe, convenient, and results in PRs at least as good as in the natural cycle. It may be of particular value in patients with an irregular cycle or in those for whom prolonged monitoring is undesirable.

The effect of cigarette smoking on ovarian function and early pregnancy outcome of in vitro fertilization treatment.

A retrospective analysis of the results of the first attempt at in vitro fertilization (IVF) treatment in 447 couples was performed by chart review. In 124 couples the female partners smoked cigarettes, and in 236 couples they did not. A total of 69 pregnancies (19.2%) were achieved, 50 in nonsmokers (21.2% per cycle), and 19 in smokers (15.3% per cycle). There were no significant differences in these cycles between the two groups in peak estradiol level achieved, the number of eggs retrieved, fertilization rate, or implantation rate. The incidence of spontaneous abortion was higher in smokers (42.1%) than in nonsmokers (18.9%). Consequently, the delivery rate per cycle of IVF was significantly lower in the smoking group (11 of 124, 9.6%) than in the nonsmokers (40 of 236, 17.0%). There was no effect when only the husband was a smoker. From these data, smoking appears to significantly reduce the chances of successful pregnancy after IVF treatment.

Is diagnostic hysteroscopy adhesiogenic?

To determine whether diagnostic hysteroscopy posed any risk of causing the formation of intrauterine adhesions 108 women were studied. Diagnostic hysteroscopy was performed; following tubal surgery, a second-look hysteroscopy was undertaken. Adhesion were noted in 1 of 100 of those patients in whom no prior adhesions had been noted.

Therapeutic donor insemination with frozen semen.

Although it is now accepted that cryopreserved semen must, on ethical and medicolegal grounds, be used for donor insemination many clinicians still believe that it has an unacceptably reduced fecundability rate as compared with fresh semen. We studied the outcome of 81 recipients who started therapeutic donor insemination (TDI) treatment during 1986 in a program that used exclusively cryopreserved semen; 55 had never undergone TDI and were receiving the first series (six cycles), 6 were receiving the second series (also six cycles), and 20 had achieved pregnancy through TDI previously and were starting the treatment again. Insemination with semen stored in 0.5-ml French straws was performed daily during the periovulatory period while the modified Insler score was 10 or greater out of 15. A total of 42 (52%) of the recipients became pregnant within six TDI cycles; 4 (10%) had a spontaneous abortion. An average of 4.8 straws were used per cycle among those who became pregnant and 5.1 per cycle among those who did not. On average 2.6 cycles were required to achieve pregnancy. The overall fecundability rate was 14.6%. We conclude that a TDI program involving exclusively frozen semen can be operated with a success rate comparable to rates achieved with fresh semen if a simple, established cryopreservation method and an uncomplicated clinical management protocol are used.

Transient hyperprolactinemia has no effect on endocrine response and outcome in in vitro fertilization (IVF).

Transient rises in plasma prolactin levels can be observed during the late follicular phases of both natural and stimulated cycles. It has been suggested that such a phenomenon might adversely affect the success of in vitro fertilization. This prospective study was designed to assess the effect of transient rises in prolactin levels on the endocrine response to ovarian stimulation and the outcome of in vitro fertilization treatment. A total of 90 treatment cycles in 87 couples was studied. Prolactin was measured in the mid and late follicular phases of the cycles. During the study period, 24 pregnancies occurred. There were no differences in those cycles in which pregnancy did or did not occur in either mid or late follicular prolactin levels. Neither the initial level nor the percentage rise in prolactin during the stimulation had any effect on the peak estradiol level achieved, the numbers of follicles seen, the number of eggs retrieved, or the incidence or outcome of pregnancy. It was concluded that transient hyperprolactinemia is of no significance in ovarian stimulation for in vitro fertilization.