Cognitive flexibility and suicide risk indicators among psychiatric inpatients.

Cognitive flexibility has been linked with positive psychological health outcomes, whereas cognitive rigidity has been linked with suicide risk. We examined associations among cognitive flexibility and certain suicide risk indicators among a sample of patients psychiatrically hospitalized for suicide risk (n = 40). Data were collected during two pilot randomized controlled trials. At baseline, cognitive flexibility was not associated with depressive symptoms, hopelessness, or severity of lifetime worst point suicide ideation. At 3-months post psychiatric discharge, higher baseline cognitive flexibility predicted significantly lower depressive symptoms and worst point suicide ideation in the past month, but did not predict lower hopelessness.

Inpatient psychiatric care following a suicide-related hospitalization: A pilot trial of Post-Admission Cognitive Therapy in a military medical center.

OBJECTIVE: Individuals with a recent suicidal crisis are typically admitted for inpatient psychiatric care. However, targeted inpatient interventions for suicide prevention remain sparse. Thus, this pilot randomized controlled trial evaluated a brief inpatient cognitive behavioral protocol, Post-Admission Cognitive Therapy (PACT) for the prevention of suicide. METHODS: United States service members and beneficiaries (N = 24) psychiatrically hospitalized at a military medical center due to a recent suicidal crisis were randomized to receive either PACT plus Enhanced Usual Care (PACT + EUC) or EUC alone. Blinded follow-up assessments were conducted at one-, two-, and three-months post discharge. The degree of change and variability of response to PACT for repeat suicide attempt(s) (primary outcome), as well as depression, hopelessness, and suicide ideation (secondary outcomes) were examined. RESULTS: Significant between-group differences in re-attempt status were not found. Reliable Change Index analyses indicated that among the most clinically severe participants, a greater proportion of PACT + EUC participants compared with EUC participants met criteria for clinically significant reductions on depression (40% versus 25%), hopelessness (67% versus 50%), suicide ideation (45% versus 33%), and posttraumatic stress symptomatology (40% versus 25%). CONCLUSIONS: PACT is a promising inpatient cognitive behavioral intervention for suicide risk reduction. The efficacy of PACT is currently being evaluated in a well-powered multi-site randomized controlled trial.

Pilot trial of post-admission cognitive therapy: Inpatient program for suicide prevention.

Suicide remains a significant public health problem for the United States military. Trauma-related diagnoses such as acute stress disorder (ASD) or posttraumatic stress disorder (PTSD) may exacerbate suicide risk, particularly among service members psychiatrically hospitalized following suicide-related events. To date, treatments to address suicide risk and trauma symptomatology among service members within inpatient milieus have been nonexistent. To address this gap, a randomized controlled pilot trial of Post-Admission Cognitive Therapy (PACT) was conducted to evaluate a targeted cognitive-behavioral program among traumatized military personnel (N = 36) hospitalized following a recent suicide attempt. All participants met criteria for ASD or PTSD and were randomly assigned to receive either PACT and enhanced usual care (PACT + EUC) or EUC alone. PACT consisted of six 60- to 90-min individual psychotherapy sessions, adapted from Brown et al.'s (2005) cognitive therapy protocol for suicide prevention. Blinded follow-up assessments were conducted at 1-, 2-, and 3-months postpsychiatric discharge. The primary outcome was days until repeat suicide attempt. Secondary outcomes included depression, hopelessness, suicide ideation, and PTSD symptoms. Participants did not significantly differ in reattempt status. However, based on reliable change index analyses, a greater proportion of PACT + EUC versus EUC participants met criteria for clinically significant change on measures of depression (100% vs. 78%), hopelessness (83% vs. 57%), and PTSD symptom severity (100% vs. 38%), but not for suicide ideation (60% vs. 67%). PACT is an innovative inpatient protocol, currently under evaluation in a well-powered multisite RCT for its efficacy in reducing subsequent suicidal behaviors. (PsycINFO Database Record

Motor impulsivity differentiates between psychiatric inpatients with multiple versus single lifetime suicide attempts.

A history of multiple suicide attempts conveys greater risk for suicide than a single attempt. Impulsivity may partially explain the association between multiple attempts and increased risk. We examined trait impulsivity, ability to engage in goal-directed behaviors, and impulse control among psychiatrically hospitalized United States military personnel and their dependents. Individuals with a history of multiple versus single attempts had significantly higher motor impulsivity, indicating spur of the moment action. Providers are encouraged to directly assess and treat motor impulsivity among suicidal individuals. Further research should explore whether motor impulsivity is a mechanism of change in psychosocial suicide prevention interventions.

How Parental Reactions Change in Response to Adolescent Suicide Attempt.

This study examined parental reactions to adolescents' suicide attempts and the association of reactions with future suicidal self-directed violence. Participants were 81 mothers and 49 fathers of 85 psychiatric inpatient adolescents. Maternal hostility and paternal anger and arguing predicted future suicide attempts. From pre- to post-attempt, mothers reported feeling increased sadness, caring, anxiety, guilt, fear, and being overwhelmed; fathers reported increased sadness, anxiety, and fear. Findings have clinical implications; improving parent-child relationships post-suicide attempt may serve as a protective factor for suicide.

An investigation into the potential use of serum Hsp70 as a novel tumour biomarker for Hsp90 inhibitors.

Hsp90 inhibitors are under investigation in multiple human clinical trials for the treatment of cancers, including myeloma, breast cancer, prostate, lung, melanoma, gastrointestinal stromal tumour and acute myeloid leukaemia. The pharmacodynamic activity of Hsp90 inhibitors in the clinic is currently assessed by Hsp70 induction in peripheral blood mononuclear cells using Western blot analysis, a method that is laborious, semiquantitative and difficult to implement in the clinic. Since Hsp70 was reported to be secreted by tumour cells and elevated in sera of cancer patients, serum Hsp70 has been evaluated as a potentially more robust, easily and reproducibly measured biomarker of Hsp90 inhibition as an alternative to cytosolic Hsp70. A highly sensitive and specific electrochemiluminescent ELISA was developed to measure serum Hsp70 and employed to evaluate Hsp70 levels in both ex vivo and xenograft samples. In ex vivo studies, maximal secretion of Hsp70 by tumour cells was observed between 48 and 72 h after exposure to Hsp90 inhibitors. In in vivo studies a 3-4-fold increase in serum Hsp70 was observed following treatment with BIIB021 in tumour-bearing mice. Strikingly, secreted Hsp70 was detectable in mice transplanted with human tumours but not in naive mice indicating a direct origination from the transplanted tumours. Analysis of clinical samples revealed low baseline levels (2 - 15 ng ml(-1)) of Hsp70 in the serum of cancer patients and normal donors. Together these findings in laboratory studies and archived cancer patient sera suggest that serum Hsp70 could be a novel biomarker to assess reliably the pharmacological effects of Hsp90 inhibitors in clinical trials, especially under conditions where collection of tumour biopsies is not feasible.

BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.

17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis.

BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.

Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.

Identification of new biomarkers for clinical trials of Hsp90 inhibitors.

The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive. We have identified two new biomarkers [insulin-like growth factor binding protein-2 (IGFBP2) and HER-2 extracellular domain] that can be readily detected in patient sera by ELISA. Both secreted proteins are derived from or regulated by Hsp90 client proteins, raising hopes that they might be sensitive serum markers of HSP90 inhibitor activity. Several structurally unrelated HSP90 inhibitors dose-dependently decreased secretion of both IGFBP-2 and HER-2 extracellular domain into culture medium, and both proteins were more sensitive to HSP90 inhibitors than previously identified biomarkers. In sera from BT474 tumor-bearing mice, both IGFBP-2 and HER-2 extracellular domain were down-regulated by 17-AAG in a time-dependent and dose-dependent manner, coincident with the degradation of HER-2 and attenuation of AKT activity in the tumors. Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response. In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors.