Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRI-antipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.     

Transrectal ultrasonographically assisted radical retropubic prostatectomy.

Radical prostatectomy is associated with difficulty in determining the division site of the urethra adjacent to the apical region of the prostate. We present the results of a feasibility clinical trial in three patients to determine whether intraoperative transrectal ultrasonography may assist during radical retropubic prostatectomy. Using this technique the apex is readily identified and a detailed view of the urethral stump could be obtained. In one case residual apical tissue was identified and excised. The creation of the vesicourethral anastomosis was documented and its water tightness was demonstrated. We conclude that transrectal ultrasonography can be performed during radical retropubic prostatectomy and may be helpful in selected cases.     

Calcium dependence of serotonin-evoked conductance in C6 glioma cells.

Whole-cell membrane currents and imaging of intracellular calcium concentrations ([Ca2+]i) were used to investigate the role of calcium in a response to serotonin of C6 glioma cells. Activation of a high-affinity serotonin receptor induced a transient rise in calcium concentration in these cells and activated a predominantly potassium conductance, with a small chloride component. Perfusion of the cytoplasm with an internal solution containing high calcium concentration induced similar but prolonged increase of membrane conductance. The responsiveness of C6 cells to serotonin was negatively correlated with the concentration of the unbound calcium chelator BAPTA when BAPTA-buffered calcium-containing intracellular solutions were used. Responses to serotonin persisted in the absence of external calcium, decreased gradually, and then recovered partially after replenishment of extracellular calcium. These findings substantiate the direct role of intracellular calcium in mediating the serotonin response, and indicate that serotonin-induced release of calcium from intracellular stores is sufficient for the activation of conductance in the C6 glioma cell line.     

Pineal germinoma with unilateral blindness. Seeding of germinoma cells in optic nerve sheath

A 13-year-old boy presented with blindness and loss of the papillomacular bundle in the left eye, bilateral papilledema sparing the area of axonal loss, and Parinaud's syndrome. Computerized tomography (CT) revealed an enlarged kinked left optic nerve and enlarged optic canal as well as a tumor in the pineal area producing hydrocephalus. Magnetic resonance (MR) scans showed multiple spinal metastases. The histological diagnosis was germinoma. On completion of four courses of chemotherapy with cis-platin, vinblastine, and bleomycin, repeated CT of orbita and MR imaging of the spine demonstrated the disappearance of the tumor surrounding the left optic nerve and of the spinal metastases. This is believed to be the first case report of seeding of germinoma into the perioptic arachnoid space.     

Varicocele in youth. A therapeutic dilemma.

The need for treatment of asymptomatic varicocele in youth is controversial. In the current study testicular volume and seminal variables were evaluated in three groups: young varicocele patients with undetermined fertility potential, infertile varicocele patients, and a control group of young males. The testicular volume was determined by ultrasonographic measurements. The results revealed a significant loss of "testicular mass" in both varicocele groups compared with the control group. The seminal findings disclosed a severe disturbance of spermatogenesis in the older varicocele group, whereas in the younger varicocele patients only the total spermatic count was significantly depressed. This difference in severity of functional impairment between the younger and older varicocele groups possibly points towards progressiveness of damage to the testicles. A more decisive therapeutic approach to the young male with asymptomatic varicocele and unknown fertility status could be justified.     

Blastocyst development and birth after in-vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching

Immature oocyte recovery followed by in-vitro oocyte maturationand in-vitro fertilization is a promising new technology forthe treatment of human infertility. The technology is attractiveto potential oocyte donors and infertile couples because ofits reduced treatment intervention. Immature oocytes were recoveredby ultrasoundguided transvaginal follicular aspiration. Oocyteswere matured in vitro for 36–48 h followed by intracytoplasmicsperm injection (ICSI). Embryos were cultured in vitro for 3or 5 days before replacement. Assisted hatching was performedon a day 5 blastocyst stage embryo. Embryo and uterine synchronywere potentially enhanced by luteinization of the dominant follicleat the time of immature oocyte recovery. Mature oocyte and embryoproduction from immature oocyte recovery were similar to theprevious IVF results of the patients. A blastocyst stage embryo,produced as a result of in-vitro maturation, ICSI, in-vitroculture and assisted hatching, resulted in the birth of a healthybaby girl at 39 weeks of gestation.