Eugene H. Rubin

Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial.

Objective Depression is a prevalent and chronic condition in diabetes and is associated with poor glucose regulation and poor compliance with diabetes treatment. This investigation evaluated the effects of nortriptyline on depression and glycemic control to see whether depression in diabetes is treatable and whether restoring mental health contributes to improved medical outcome. Method: Sixty-eight diabetic patients with poor glycemic control, 28 of whom had active major depression (DSM-IIIR), completed a randomized, placebo-controlled, double-blind trial involving 8 weeks of treatment with nortriptyline targeted to therapeutic plasma levels (50-150 ng/ml). Depression improvement was determined with the Beck Depression Inventory; glucose control was measured by glycated hemoglobin levels. Compliance behavior was assessed using medication dispensing devices and glucometers equipped with electronic memory. Results: The reduction in depression symptoms was significantly greater in depressed patients treated with nortriptyline compared with those receiving placebo (-10.2 vs -5.8, p =.03). Nortriptyline was not statistically superior to placebo in reducing glycated hemoglobin of the depressed subjects (p =.5). However, path analysis indicated that the direct effect of nortriptyline was to worsen glycemic control whereas depression improvement had an independent beneficial effect on glycated hemoglobin. These findings were not explained by the relationships of nortriptyline treatment to weight change (r = -0.21, p =.31) or depression improvement to compliance with the protocol for self-monitoring of blood glucose (r = 0.01, p =.97). Conclusions: Major depression in diabetic patients can be effectively treated with nortriptyline at the expense of a direct hyperglycemic effect. Path analysis demonstrated a treatment-independent effect of depression improvement on glycemic control, suggesting that a more ideal antidepressant agent may both restore mental health and improve medical outcome.

Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type

Delusions, misidentifications and hallucinations occur frequently throughout the course of senile dementia of the Alzheimer type (SDAT). Rates of psychosis among subjects with moderate to severe SDAT range from 42% to 84% in our study group; at least half of persons with SDAT with no prior psychiatric history will display psychosis at some point during the course of dementia. Furthermore, psychotic symptoms are associated with accelerated cognitive deterioration, but not with increased mortality.

Treatment of Depression After Coronary Artery Bypass Surgery: A Randomized Controlled Trial

CONTEXT There has been little research on the treatment of depression after coronary artery bypass surgery. OBJECTIVE To test the efficacy of 2 nonpharmacological interventions for depression after coronary artery bypass surgery compared with usual care. DESIGN A 12-week, randomized, single-blind clinical trial with outcome evaluations at 3, 6, and 9 months. SETTING Outpatient research clinic at Washington University School of Medicine, St Louis, Missouri. PATIENTS One hundred twenty-three patients who met the DSM-IV criteria for major or minor depression within 1 year after surgery. INTERVENTION Twelve weeks of cognitive behavior therapy or supportive stress management. Approximately half of the participants were taking nonstudy antidepressant medications. MAIN OUTCOME MEASURE Remission of depression, defined as a score of less than 7 on the 17-item Hamilton Rating Scale for Depression. RESULTS Remission of depression occurred by 3 months in a higher proportion of patients in the cognitive behavior therapy (71%) and supportive stress-management (57%) arms than in the usual care group (33%) (chi(2)(2) = 12.22, P = .002). Covariate-adjusted Hamilton scores were lower in the cognitive behavior therapy (mean [standard error], 5.5 [1.0]) and the supportive stress-management (7.8 [1.0]) arms than in the usual care arm (10.7 [1.0]) at 3 months. The differences narrowed at 6 months, but the remission rates differed again at 9 months (73%, 57%, and 35%, respectively; chi(2)(2) = 12.02, P = .003). Cognitive behavior therapy was superior to usual care at most points on secondary measures of depression, anxiety, hopelessness, stress, and quality of life. Supportive stress management was superior to usual care only on some of the measures. CONCLUSIONS Both cognitive behavior therapy and supportive stress management are efficacious for treating depression after coronary artery bypass surgery, relative to usual care. Cognitive behavior therapy had greater and more durable effects than supportive stress management on depression and several secondary psychological outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00042198.

The nature of psychotic symptoms in senile dementia of the Alzheimer type.

The Alzheimer Disease Research Center at Washington Universitys medical school has gathered a large sample of subjects with senile dementia of the Alzheimer type (SDAT) who are free of other potentially complicating medical, neurologic and psychiatric disorders. Using this homogeneous population, we have characterized psychotic symptoms associated with SDAT. Three groups of symptoms occur commonly: paranoid delusions, misidentification syndromes, and hallucinations. The nature and frequency of these syndromes are discussed. (J Geriatr Psychiatry Neurol 1988;1:16-20).

The Progression of Personality Changes in Senile Dementia of the Alzheimer's Type

Passive, agitated, and self‐centered behavioral changes were noted on initial evaluation in two‐thirds, one‐third, and one‐third, respectively, of subjects with mild senile dementia of the Alzheimers type (SDAT). Over a 50‐month follow‐up period, the percentage of patients who exhibited agitated and self‐centered behaviors doubled. The percentage of subjects who demonstrated all three behavioral changes increased from 11% at entry to the study (mild SDAT) to over 50% when the dementia had reached a severe stage. The presence of personality changes at a mild stage of dementia did not predispose subjects to more rapid progression to a more advanced stage of illness.

Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial.

CONTEXT Studies of depressed psychiatric patients have shown that antidepressant efficacy can be increased by augmentation with omega-3 fatty acids. OBJECTIVE To determine whether omega-3 improves the response to sertraline in patients with major depression and coronary heart disease (CHD). DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial. Between May 2005 and December 2008, 122 patients in St Louis, Missouri, with major depression and CHD were randomized. INTERVENTIONS After a 2-week run-in period, all patients were given 50 mg/d of sertraline and randomized in double-blind fashion to receive 2 g/d of omega-3 acid ethyl esters (930 mg of eicosapentaenoic acid [EPA] and 750 mg of docosahexaenoic acid [DHA]) (n=62) or to corn oil placebo capsules (n=60) for 10 weeks. MAIN OUTCOME MEASURES Scores on the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HAM-D). RESULTS Adherence to the medication regimen was 97% or more in both groups for both medications. There were no differences in weekly BDI-II scores (treatment x time interaction = 0.02; 95% confidence interval [CI], -0.33 to 0.36; t(112) = 0.11; P = .91), pre-post BDI-II scores (placebo, 14.8 vs omega-3, 16.1; 95% difference-in-means CI, -4.5 to 2.0; t(116) = -0.77; P = .44), or HAM-D scores (placebo, 9.4 vs omega-3, 9.3; 95% difference-in-means CI, -2.2 to 2.4; t(115) = 0.12; P = .90). The groups did not differ on predefined indicators of depression remission (BDI-II < or = 8: placebo, 27.4% vs omega-3, 28.3%; odds ratio [OR], 0.96; 95% CI, 0.43-2.15; t(113) = -0.11; P = .91) or response (> 50% reduction in BDI-II from baseline: placebo, 49.0% vs omega-3, 47.7%; OR, 1.06; 95% CI, 0.51-2.19; t(112) = 0.15; P = .88). CONCLUSIONS Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks, compared with sertraline and placebo. Whether higher doses of omega-3 or sertraline, a different ratio of EPA to DHA, longer treatment, or omega-3 monotherapy can improve depression in patients with CHD remains to be determined. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116857.

Behavioral changes in patients with mild senile dementia of the Alzheimer's type

Behavioral changes in 44 subjects with well-characterized mild senile dementia of the Alzheimers type (SDAT) and 16 subjects with only questionable SDAT were compared to a control group of 58 subjects. Answers to both open-ended questions and personality items from the Blessed Dementia Scale were examined. Seventeen items were classified into seven categories by factor analysis and then further categorized into four clinically useful groups: passive, agitated, self-centered, and suspicious. Over 75% of subjects with mild SDAT had behavioral changes compared to 10% of controls. Passive symptoms were the most common, occurring in two-thirds of mild SDAT subjects. Agitated and self-centered symptoms were also common, occurring half as frequently as passive symptoms. Passive symptoms occurred alone in 25% of those with mild SDAT, whereas passive symptoms, together with agitated and/or self-centered symptoms, were present in 11-16% of subjects with mild SDAT. Agitated or self-centered symptoms rarely occurred alone. Characterizing the behavioral symptoms of SDAT is important for their clinical implications and for an approach to understanding brain-behavioral relationships.

Influence of divalent cations on regulation of cyclic GMP and cyclic AMP levels in brain tissue.

—Depolarizing concentrations of K+ elevate levels of both adenosine 3′,5′monophosphate (cyclic AMP) and guanosine 3′,5′monophosphate (cyclic GMP) in incubated slices of mouse cerebellum. Calcium is an essential requirement for the K+ ‐induced accumulation of cyclic GMP. Barium and Sr2+, but not Mn2+ or Co2+, can substitute for Ca2+ in this process. Relatively high concentrations of Mg2+ inhibit the effect of Ca2+ on K+‐induced accumulation of cyclic GMP. In contrast, depolarizing concentrations of K+ are capable of elevating cyclic AMP levels in brain slices suspended in media containing Mg2+ and no other divalent cations. High concentrations of Ca2+ (1 mm or greater) augment this Mg2+ ‐dependent, K+‐induced accumulation of cyclic AMP, however. Strontium and Mn2+, but not Ba2+ or Co2+, can substitute for Ca2+ in this process, and high concentrations of Mg2+ are not inhibitory. The divalent cation ionophore, A‐23187 (10 μm), in the presence of extracellular Ca2+ elevates the level of cyclic GMP, but not cyclic AMP, in incubated mouse cerebellum slices.

Symptoms Of “depression” In Dementia Of The Alzheimer Type

The frequency of symptoms of depression (Feighner criteria) was evaluated in subjects with dementia of the Alzheimer type (DAT) and matched controls enrolled in a longitudinal natural history study of DAT. Despite enrollment criteria which excluded subjects with affective disorders, the collateral sources of subjects with DAT described these subjects as having significantly more “depressive” symptoms than controls without dementia at entry, and at 15− and 34-month follow-up. The collateral sources of the subjects with DAT reported that these demented individuals experienced significantly greater loss of interest, decreased energy, difficulty in thinking and concentrating, and psychomotor agitation or retardation then did the control group. The subjects with DAT reported fewer symptoms than did their collateral sources, but like their collateral sources, they did not report a global elevation of all Feighner symptoms, but rather related significantly greater difficulty in thinking and concentrating than the controls and a tendency toward loss of interest and psychomotor changes. No subject became clinically depressed.The results suggest a significant overlap between the symptoms of dementia and depression. The frequency with which the above symptoms occur in DAT confounds the use of Feighner and, by extension, DSM-III criteria in diagnosing depression in cognitively impaired individuals with DAT.

Distribution and regulation of cyclic nucleotide levels in cerebellum, in vivo.

Abstract— In mouse cerebellum, in vivo. cyclic GMP levels are 7 pmol/mg protein in the vermis and 40% lower in the hemispheres, whereas cyclic AMP levels are 7 9 pmol/mg protein in both regions. In the vermis. most of the cyclic GMP is contained in the molecular layer; cyclic AMP levels are highest in the granular layer. Amphetamine, harmaline. pentylenetetrazol and physical shaking elevate, and diazepam and reserpine depress levels of cyclic GMP in both vermis and hemispheres. Oxotremorine and atropine, respectively, increase and decrease cyclic GMP levels only in vermis. Regardless of the agent used, most of the change (67 89%) in cyclic GMP levels occurs in the molecular layer of the vermis; the remainder occurs in the granular layer. Of the drugs tested, only pentylenetetrazol affects cyclic AMP levels, and this drug increases cyclic AMP levels in both vermis and hemispheres and causes equal elevations in the molecular and granular layers of the vermis. In incubated slices of mouse cerebellum, none of the drugs produces changes in cyclic nucleotide levels which are similar to those in vivo. These data indicate that many drugs and conditions that alter cyclic GMP levels in cerebellum act via a common, but indirect, process.