The additional loss of Bak and not the lack of the protein tyrosine kinase p56/Lck in one JCaM1.6 subclone caused pronounced apoptosis resistance in response to stimuli of the intrinsic pathway.

Ionising radiation, hypoxia, and the cyclooxygenase-2 inhibitor Celecoxib are known agonists of the intrinsic apoptosis pathway that involves mitochondrial damage upstream of caspase activation. Mitochondrial integrity is regulated by the pro-apoptotic Bcl-2 protein family members Bak and Bax. Upstream of the mitochondria, many kinases and phosphatases control the apoptotic response. However, the role of the non-receptor tyrosine kinase p56/Lck during apoptosis is controversial. The present investigation demonstrate the existence of two JCaM1.6 subclones, one expressing and one deficient for Bak. The lack of p56/Lck expression in JCaM1.6 cells per se did hardly affect apoptosis induced by ionising radiation, hypoxia, or Celecoxib. Only the additional loss of Bak expression, as observed in one JCaM1.6 subclone, rendered the cells resistant. siRNA-mediated downregulation of Bak and p56/Lck mimicked the observed effects in the subclones. Earlier experiments performed with the Bak-negative clone might have lead to the wrong assumption that lack of p56/Lck alone, and not the additonal loss of Bak, was responsible for reduced sensitivity towards stimuli of the intrinsic apoptosis pathway.

Clozapine as add-on medication in the maintenance treatment of bipolar and schizoaffective disorders. A case series.

Atypical neuroleptics are increasingly used in the treatment of bipolar and schizoaffective disorders. Currently, numerous controlled short-term studies are available for clozapine, olanzapine, risperidone or quetiapine, but long-term data are still missing. Three patients (2 with bipolar disorder, 1 with schizoaffective disorder) are described who showed a marked reduction of affective symptomatology after clozapine had been added to mood stabilizer pretreatment. The patients were seen once a month before and after the introduction of clozapine for at least 6 months. Treatment response was evaluated using different rating scales (IDS, YMRS; GAF; CGI-BP) and the NIMH Life Chart Methodology. All patients showed a marked improvement after the add-on treatment with clozapine had been initiated. Clozapine was tolerated well with only transient and moderate weight gain and fatigue as only side effects. This case series underlines the safety and efficacy of clozapine as add-on medication in the treatment of bipolar and schizoaffective disorders.

The Stanley Foundation Bipolar Network: results of the naturalistic follow-up study after 2.5 years of follow-up in the German centres.

The Stanley Foundation Bipolar Network (SFBN) is an international, multisite network investigating the characteristics and course of bipolar disorder. Methods (history, ratings and longitudinal follow-up) are standardized and equally applied in all 7 centres. This article describes demographics and illness characteristics of the first 152 German patients enrolled in the SFBN as well as the results of 2.5 years of follow-up. Patients in Germany were usually enrolled after hospitalisation. More than 72% of the study population suffered from bipolar I disorder and 25% from bipolar II disorder. The mean +/- SD age of the study participants was 42.08 +/- 13.5 years, and the mean +/- SD age of onset 24.44 +/- 10.9 years. More than 40% of the sample reported a rapid-cycling course in history, and even more a cycle acceleration over time. 37% attempted suicide at least once. 36% had an additional Axis I disorder, with alcohol abuse being the most common one, followed by anxiety disorders. During the follow-up period, only 27% remained stable, 56% had a recurrence, 12.8% perceived subsyndromal symptoms despite treatment and regular visits. 27% suffered from a rapid-cycling course during the follow-up period. Recurrences were significantly associated with bipolar I disorder, an additional comorbid Axis I disorder, rapid cycling in history, a higher number of mood stabilizers and the long-term use of typical antipsychotics. Rapid cycling during follow-up was only associated with a rapid-cycling course in history, a higher number of mood stabilizers and at least one suicide attempt in history.