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.     

Patterns of hearing loss and psychiatric morbidity in elderly patients attending a hearing clinic

This study examines the relationship between hearing loss and psychiatric diagnosis in a geriatric population attending a hearing clinic. Major depression was the most frequent psychiatric disorder and was diagnosed in 30% of subjects. A sensorineural type hearing loss was diagnosed in 85% of the depressed subjects. More hearing loss was seen in subjects with onset of depression after age 55 years, in comparison to geriatric patients with depression onset before age 55 years, subjects with other psychiatric disorders and subjects without a psychiatric diagnosis (p <0.001). The audiogram and speech audiometry suggest involvement of auditory nerve and central auditory pathways in late onset depression.     

Headache in lacunar stroke

The presence of headache within a 72-h interval of stroke onset was investigated in a cohort of 145 lacunar infarcts. Fourteen (10%) experienced diffuse or bilateral headache. Hypertension was less frequent (43 vs 76%; 95% CI: 6 to 60%) and of shorter duration (2.4 vs 7.8 years; t = 2.29; p = 0.02) among patients with headache. Leukoaraiosis was less frequent (40% vs 71%; 95% CI: −57 to −7%) and severe (7 vs 24%; 95% CI: −33 to −2%) in patients with headache. Age, sex, stroke risk factors, type of lacunar stroke, mode of onset, stroke severity, ultrasound and other CT findings were similar in patients with and without headache. No differences in the sixth month neurological or functional outcome were detected between lacunar patients with and without headache. Headache in lacunar stroke cannot be predicted by the clinical characteristics of the stroke and is not due to coexisting cardiembolism, intra or extracranial disease. Hypertensive small-vessel disease is less common and severe in lacunar strokes with associated headache.     

Cyclosporin nephrotoxicity in heart and lung transplant patients

Twenty-two patients with heart, lung or heart and lung transplants maintained on cyclosporin for periods ranging from 3 months to 10 years developed renal insufficiency which was investigated by renal biopsy. The histopathological changes were: (i) severe vascular and glomerular damage due to thrombotic microangiopathy (TM); (ii) a form of focal segmental glomerulosclerosis (FSGS); (iii) glomerular ischaemia. Rather than being separate entities, these changes appeared to represent a spectrum of pathology, some biopsies showing all three forms of glomerular injury. In all cases the glomerular changes were accompanied by arteriolar and arterial pathology, and we identified novel ultrastructural changes in the arteriolar endothelial basal lamina. Tubular atrophy was a consistent feature, the severity of which reflected the severity of the glomerular sclerosis, and which appeared to be a consequence of glomerular loss. Our findings are consistent with the nephrotoxic effects of cyclosporin being mediated chiefly via damage to preglomerular vessels and glomerular capillary endothelium. From an analysis of the clinical aspects of these cases, the effects of cyclosporin appear to be to some extent idiosyncratic, and therefore not entirely preventable, but strict monitoring of blood cyclosporin levels is essential to minimize the risk of permanent renal damage. Monitoring urinary protein in addition to plasma creatinine may detect the onset of FSGS, as proteinuria precedes creatinine elevation.