Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial

OBJECTIVE: This study determined the efficacy of antidepressant medication for the treatment of depression in the "old-old." METHOD: This randomized 8-week medication trial compared citalopram, 10-40 mg/day, to placebo in the treatment of patients 75 and older with unipolar depression. RESULTS: A total of 174 patients who were 58% women with a mean age of 79.6 years (SD=4.4) and a mean baseline Hamilton Depression Rating Scale score of 24.3 (SD=4.1) were randomly assigned to treatment at 15 sites. There was a main effect for site but not for treatment condition. The remission rate, defined as a final Hamilton depression scale score <10, was 35% for the citalopram and 33% for the placebo groups. However, patients with severe depression (baseline Hamilton depression scale score >24) tended to have a higher remission rate with medication than with placebo (35% versus 19%). CONCLUSIONS: In the oldest group of community-dwelling patients to be studied to date, medication was not more effective than placebo for the treatment of depression. However, given the considerable psychosocial support received by all patients, the placebo condition represents more than the ingestion of an inactive pill. Across sites, there was considerable range in response to medication, 18% to 82%, and to placebo, 16% to 80%.     

Pegylated liposomal doxorubicin hydrochloride (PLD) and paclitaxel in recurrent or metastatic head and neck carcinoma: a phase I/II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCl (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m as a 1-h infusion with escalating increments of 5 mg/m until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration.     

The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients

OBJECTIVE: Considering the limited and controversial information on the significance of the cyclin-dependent kinase inhibitor p27Kip1 in ovarian cancer, we conducted a retrospective investigation to clarify the relationships of this protein to proliferation rate, clinicopathologic variables, and prognosis of epithelial ovarian tumors. METHODS: Paraffin-embedded tissue from 43 ovarian tumors of low malignant potential (LMP) and 80 primary ovarian adenocarcinomas was stained immunohistochemically for p27Kip1, Ki-67 antigen (a marker of cell proliferation), and p53 protein. Expression of these markers was correlated with clinicopathologic features and with overall survival of patients with adenocarcinomas. RESULTS: p27Kip1 levels were significantly higher in LMP tumors as well as in low-grade, early-stage, slowly proliferating adenocarcinomas and those associated with minimal residual disease (P < 0.001). Decreased p27Kip1 expression was related to poor overall survival on its own (P = 0.0304) and, when combined, to increased proliferation rate (P = 0.0232). More importantly, in multivariate analysis, p27Kip1/Ki-67 status was independently related to survival (P = 0.040) along with histologic type and FIGO stage. CONCLUSION: Decreased p27Kip1 expression is related to several clinicopathologic indicators of aggressiveness in ovarian adenocarcinomas and is a major player in cell cycle control in these neoplasms. On the contrary, deregulation of the protein does not seem to participate in the pathogenesis of LMP tumors. Furthermore, combined p27Kip1/Ki-67 expression is a better prognostic marker than expression of p27Kip1 or Ki-67 alone and supplements the prognostic information gained from traditional prognosticators.     

Genetic follow-up of male offspring born by ICSI,using a multiplex fluorescent PCR-based test for Yq deletions

De-novo deletions involving AZFa, b, c and d are one of the most common chromosomal aberrations in man resulting in defective spermatogenesis and male infertility. Currently, Yq deletion screening involves either single or multiplex PCR using Y-specific sequence tagged site markers and the subsequent analysis of the amplification products on ethidium bromide-stained agarose gels. To improve the practicality of routine and high throughput Yq testing, we have developed a more sensitive multiplex fluorescent (FL)-PCR screening system using genomic DNA extracted from cheek buccal cells as a readily available PCR template. For genetic follow-up studies of ICSI-conceived children, we also developed a DNA fingerprinting system based on the co-amplification of four highly polymorphic markers to validate family samples and detect any potential extraneous DNA contamination that could cause a misdiagnosis. Multiplex FL-PCR analysis of buccal cell DNA from two infertile men who conceived three sons by ICSI demonstrated that their Yq deletions were vertically transmitted. Fine mapping with additional Yq markers revealed identical deletion endpoints involving the loss of AZFdc sequences. This firstly indicates that the extent of the Yq deletion was unchanged on ICSI transmission and secondly supports the view that AZFdc deletions may arise by a common de-novo event. Analysis of paternal, maternal and sibling DNA fingerprints showed the co-inheritance of parental alleles by each male child and confirmed the expected relationship between each family member. The application of these new FL-PCR based screening tests in genetic follow-up studies will assist in confirming transmission of specific genetic defects to male offspring conceived by ICSI and provide a basis for genetic counselling and potential treatment options as these boys approach sexual maturity.     

Pharmacotherapy of depression in older patients: a summary of the expert consensus guidelines

Depression in older adults increases disability, medical morbidity, mortality, suicide risk, and healthcare utilization. Most studies of antidepressants are conducted in younger adults, and clinicians often have to extrapolate from findings in populations that do not present the same problems as older patients. Older patients often have serious coexisting medical conditions that may contribute to or complicate treatment of depression; they tend to take multiple medications, some of which may contribute to depression or interact with antidepressants; and they metabolize medications slowly and are more sensitive to side effects than younger patients. To address clinical questions not definitively answered in the research literature, the authors surveyed 50 experts on the pharmacotherapy of depressive disorders in older patients. The survey contained 64 questions with 857 options: 618 of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions; for the other 239 options, the experts were asked to write in answers or check a box. The experts reached consensus on 89% of the options rated on the 9-point scale. Categorical rankings (first line/preferred, second line/alternate, third line/usually inappropriate) were assigned to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for common and important clinical scenarios. The authors summarize the expert consensus methodology and the experts' recommendations and discuss how they relate to research findings. The experts recommend including both antidepressant medication and psychotherapy in treatment plans for nonpsychotic unipolar major depressive disorder of any severity, as well as for dysthymic disorder or persistent minor depressive disorder. They would also consider using either medication or psychotherapy alone for milder depression. For unipolar psychotic major depression, the treatment of choice is an antidepressant plus one of the newer atypical antipsychotics, with electroconvulsive therapy another first-line option. If the patient has a comorbid medical condition that is contributing to the depression, the experts recommend treating both the depression and the medical condition from the outset. The SSRIs were the top-rated antidepressants for all types of depression, with highest ratings for efficacy and tolerability given to citalopram and sertraline. Paroxetine was another first-line option, and fluoxetine was rated high second line. The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy, supportive psychotherapy, problem-solving psychotherapy, and interpersonal psychotherapy. The experts also recommended use of psychosocial interventions (e.g., psychoeducation, family counseling, visiting nurse services) in addition to pharmacotherapy and psychotherapy. Within limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction concerning common clinical dilemmas in older patients. They cannot address the complexities of each individual patient's care and can be most helpful in the hands of experienced clinicians.     

Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study

Purpose: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer.Patients and methods: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged <75 years with PS (WHO) 0–2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0–1, 16 (34%) were premenopausal and 25 (53%) had visceral disease.Results: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3–4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1–2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%–69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached.Conclusions: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.     

Docetaxel and granulocyte colony-stimulating factor in patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapy: a multicenter phase II trial

Purpose: To investigate the activity of docetaxel and granulocyte colony-stimulating factor support (G-CSF) in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with cisplatin. Patients and methods: A total of 60 patients with locoregional and metastatic NSCLC who had relapsed or progressed after first-line treatment with cisplatin-based regimens were enrolled into the trial. Docetaxel at 100 mg/m² was given as a 1-h infusion with G-CSF (rhG-CSF given s.c. at 150 μg/m²) support from day 2 to day 8 every 3 weeks; all patients received premedication with corticosteroids. Results: In all, 1 (1.6%) and 14 (23.3%) patients achieved a complete response (CR) and a partial response (PR), respectively, for an overall response rate of 25% (95% CI 14.0–35.9%); stable disease (SD) and progressive disease (PD) were documented in 18 (30%) and 27 (45%) patients, respectively. The median duration of response was 20 weeks and the median time to tumor progression was 28 weeks. The median overall survival was 32 weeks and the 1-year survival rate was 23%. A total of 263 courses were given at a median of 3 cycles/patient. Grade 3 and 4 neutropenia occurred in 11 (18%) and 14 (23%) patients, respectively, with 18 (30%) patients requiring hospitalization for neutropenic fever; 1 patient died of sepsis. Grade 2 peripheral neuropathy occurred in 9 patients (15%) and grade 3 asthenia, in 4 (7%). Other toxicities were mild. Conclusions: Docetaxel has considerable single-agent activity in patients with NSCLC who have relapsed or progressed after first-line chemotherapy with cisplatin-based regimens. Received: 17 June 1998 / Accepted: 17 August 1998     

Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression.

OBJECTIVE: The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated. METHODS: Patients with major depression aged > or =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (<50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D score < or =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo. RESULTS: The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated. CONCLUSION: In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse.