Timothy Petersen

Should More Patients Continue Aspirin Therapy Perioperatively?: Clinical Impact of Aspirin Withdrawal Syndrome

Objective:To provide an evidence-based focused review of aspirin use in the perioperative period along with an in-depth discussion of the considerations and risks associated with its preoperative withdrawal. Background:For patients with established cardiovascular disease, taking aspirin is considered a critical therapy. The cessation of aspirin can cause a platelet rebound phenomenon and prothrombotic state leading to major adverse cardiovascular events. Despite the risks of aspirin withdrawal, which are exacerbated during the perioperative period, standard practice has been to stop aspirin before elective surgery for fear of excessive bleeding. Mounting evidence suggests that this practice should be abandoned. Methods:We performed a PubMed and Medline literature search using the keywords aspirin, withdrawal, and perioperative. We manually reviewed relevant citations for inclusion. Results/Conclusions:Clinicians should employ a patient-specific strategy for perioperative aspirin management that weighs the risks of stopping aspirin with those associated with its continuation. Most patients, especially those taking aspirin for secondary cardiovascular prevention, should have their aspirin continued throughout the perioperative period. When aspirin is held preoperatively, the aspirin withdrawal syndrome may significantly increase the risk of a major thromboembolic complication. For many operative procedures, the risk of perioperative bleeding while continuing aspirin is minimal, as compared with the concomitant thromboembolic risks associated with aspirin withdrawal. Those cases where aspirin should be stopped include patients undergoing intracranial, middle ear, posterior eye, intramedullary spine, and possibly transurethral prostatectomy surgery.

Empirical testing of two models for staging antidepressant treatment resistance.

Background: An increasing amount of attention has been paid to treatment resistant depression. Although it is quite common to observe nonremission to not just one but consecutive antidepressant treatments during a major depressive episode, a relationship between the likelihood of achieving remission and ones degree of resistance is not clearly known at this time. This study was undertaken to empirically test 2 recent models for staging treatment resistance. Materials and Methods: Psychiatrists from 2 academic sites reviewed charts of patients on their caseloads. Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scales were used to measure severity of depression and response to treatment, and 2 treatment-resistant staging scores were classified for each patient using the Massachusetts General Hospital staging method (MGH-S) and the Thase and Rush staging method (TR-S). Results: Out of the 115 patient records reviewed, 58 (49.6%) patients remitted at some point during treatment. There was a significant positive correlation between the 2 staging scores, and logistic regression results indicated that greater MGH-S scores, but not TR-S scores, predicted nonremission. Conclusions: This study suggests that the hierarchical manner in which the field has typically gauged levels of treatment resistance may not be strongly supported by empirical evidence. This study suggests that the MGH staging model may offer some advantages over the staging method by Thase and Rush, as it generates a continuous score that considers both number of trials and intensity/optimization of each trial.

The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine

The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients. A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation). Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8. Patients with low folate levels (<or=2.5 ng/ml) were more likely to experience a later onset of clinical improvement than eufolatemic patients ( p =0.0028). B12 and homocysteine level status did not predict time to clinical improvement ( p >0.05). In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 1.5 wk.

The Pharmacologic Management of SSRI-Induced Side Effects: A Survey of Psychiatrists

Despite the superior side effect profile of the newer antidepressants over the tricyclics and monoamine oxidase inhibitors, all newer antidepressants are associated with a wide array of side effects. Clinicians are constantly confronted with the challenge of managing these side effects in the context of minimal research to prove one management strategy is more effective than another. The purpose of this study was to examine prescribing practices regarding the management of SSRI-associated side effects in a sample of psychiatrists attending a psychopharmacology review course. A total of 439 out of 800 clinicians (55%) attending a psychopharmacology review course responded to our questionnaire that was given prior to beginning the review course, though not all respondents answered all four items on the questionnaire. Among these items were questions designed to assess clinician preference for the management of SSRI-induced side effects. As a treatment for SSRI-induced sexual dysfunction, 43% (143/330) chose adding bupropion, while 36% (120/330) opted to switch agents as their first choice; for SSRI-induced insomnia, 78% (264/326) chose adding trazodone. Switching agents was the first choice of 61% (214/353) of clinicians for managing SSRI-induced agitation, 93% (339/363) for managing SSRI-associated weight gain. In an effort to manage most SSRI-associated side effects (with the exception of sexual dysfunction and insomnia), the majority of the clinicians responding to our survey opted to switch agents rather than add a specific medication to the existing SSRI. In our opinion, this practice may reflect the relative lack of research studies on the role of adjunctive treatments in the management of SSRI-induced side effects and/or the tendency to favor monotherapy over polypharmacy.

S-Adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: An open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine

Background: The purpose of this open trial was to evaluate the safety, tolerability, and efficacy of oral S-adenosyl-l-methionine as an antidepressant adjunct among partial and nonresponders to serotonin reuptake inhibitors or venlafaxine. Method: Thirty antidepressant-treated adult outpatients with persisting major depressive disorder received 800 to 1600 mg of S-adenosyl-l-methionine tosylate over a 6-week trial. Results: Intent-to-treat analyses based on the Hamilton Depression Rating Scale revealed a response rate of 50% and a remission rate of 43% following augmentation with S-adenosyl-l-methionine. Gastrointestinal symptoms and headaches were the most common side effects. Conclusion: Augmentation of selective serotonin reuptake inhibitors or venlafaxine with S-adenosyl-l-methionine warrants a placebo-controlled trial in resistant depression.

Lithium Augmentation of Nortriptyline for Subjects Resistant to Multiple Antidepressants

Lithium augmentation, the most studied augmentation strategy for depression, has not been evaluated in patients with a history of non-response to multiple antidepressants. The objective of this study was to assess the efficacy of lithium augmentation for patients with a history of treatment resistant depression who also failed a prospective trial of nortriptyline. We enrolled 92 subjects with treatment resistant depression. Treatment resistance was defined by at least one, but no more than five, adequate trials of antidepressants during the current episode. Subjects were treated with nortriptyline (NT) for 6 weeks. Those subjects who tolerated NT for 6 weeks and whose depression did not respond (n=35) were randomized to receive either lithium (n=18) or placebo (N=17) augmentation of nortriptyline for an additional 6 weeks. Response was defined as an equal to or greater than 50% decrease in HAM-D-17 scores. After 6 weeks of double-blind augmentation, 12.5 % of subjects responded to lithium and 20.0% to placebo. Our results revealed no significant difference between lithium and placebo augmentation. While lithium augmentation seems to be useful in depression refractory to a single medication in some studies, our data suggest limited usefulness of this option for patients refractory to multiple treatments. More definitive data await the outcome of the NIMH Sequential Treatment Alternatives to Relieve Depression (STAR*D) study.

Major Depression Symptoms in Primary Care and Psychiatric Care Settings: A Cross-Sectional Analysis

PURPOSE We undertook a study to confirm and extend preliminary findings that participants with major depressive disorder (MDD) in primary care and specialty care settings have with equivalent degrees of depression severity and an indistinguishable constellation of symptoms. METHODS Baseline data were collected for a distinct validation cohort of 2,541 participants (42% primary care) from 14 US regional centers comprised of 41 clinic sites (18 primary care, 23 specialty care). Participants met broadly inclusive eligibility criteria requiring a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of MDD and a minimum depressive symptom score on the 17-item Hamilton Rating Scale for Depression. The main outcome measures were the 30-item Inventory of Depressive Symptomatology – Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. RESULTS Primary care and specialty care participants had identical levels of moderately severe depression and identical distributions of depressive severity scores. Both primary care and specialty care participants showed considerable suicide risk, with specialty care participants even more likely to report prior suicide attempts. Core depressive symptoms or concurrent psychiatric disorders were not substantially different between settings. One half of participants in each setting had an anxiety disorder (48.6% primary care vs 51.6% specialty care, P = .143), with social phobia being the most common (25.3% primary care vs 32.1% specialty care, P = .002). CONCLUSIONS For outpatients with nonpsychotic MDD, depressive symptoms and severity vary little between primary care and specialty care settings. In this large, broadly inclusive US sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings.

Obesity among outpatients with Major Depressive Disorder

Studies focusing on the prevalence of obesity in Major Depressive Disorder (MDD), or the impact of excess body fat on the treatment of MDD are lacking. The aim of the present work is to systematically study obesity in MDD outpatients. A total of 369 MDD outpatients enrolled in an 8-wk trial of 20 mg fluoxetine had height and weight measured at baseline. We then examined: (1) the prevalence of being overweight or obese, (2) the relationship between obesity and a number of demographic and clinical variables, and, (3) the relationship between relative body weight and obesity with clinical response. We found that more than 50% of patients were overweight [body mass index (BMI) > or =2 5 kg/m2], while 20% were obese (BMI > or = 30 kg/m2). Obese patients presented with worse somatic well-being scores than non-obese MDD patients, but they did not differ with respect to depression severity, anxiety, somatic complaints, hopelessness or hostility. Greater relative body weight, but not obesity, predicted non-response. In conclusion, greater relative body weight was found to place MDD outpatients at risk for fluoxetine resistance.

Psychosocial functioning during the treatment of major depressive disorder with fluoxetine

Background: Major depressive disorder (MDD) is associated with significant disability, having a profound impact on psychosocial functioning. Therefore, studying the impact of treatment on psychosocial functioning in MDD could help further improve the standard of care. Methods: Two hundred twenty-two MDD outpatients were treated openly with 20 mg fluoxetine for 8 weeks. The self-report version of the Social Adjustment Scale was administered at baseline and during the final visit. We then tested for the relationships between (1) self-report version of the Social Adjustment Scale scores at baseline and clinical response, (2) nonresponse, response and remission status and overall psychosocial adjustment at end point, (3) the number/severity of residual depressive symptoms and overall psychosocial adjustment at end point in responders, and (4) the time to onset of response and overall psychosocial adjustment at end point. Results: An earlier onset of clinical response predicted better overall psychosocial functioning at end point (P = 0.0440). Responders (n = 128) demonstrated better overall psychosocial adjustment at end point than nonresponders (P = 0.0003), while remitters (n = 64) demonstrated better overall psychosocial adjustment at end point than nonremitted responders (P = 0.0031). In fact, a greater number/severity of residual symptoms predicted poorer overall psychosocial adjustment at end point in responders (P = 0.0011). Psychosocial functioning at baseline did not predict response. Conclusions: While MDD patients appear equally likely to respond to treatment with fluoxetine, regardless of their level of functioning immediately before treatment, the above results stress the importance of achieving early symptom improvement then followed by full remission of depressive symptoms with respect to restoring psychosocial functioning in MDD.

Cardiovascular risk factors may moderate pharmacological treatment effects in major depressive disorder

Objective: An increased association between depression and cardiovascular disease, as well as cardiovascular risk factors, led to the “vascular depression” hypothesis. This subtype of depression is postulated to have a different clinical presentation and to be more treatment-resistant. In this study, we measured the impact of cardiovascular risk factors on the outcome of antidepressant treatment in major depressive disorder (MDD). Method: We enrolled 348 MDD subjects, ages 19 to 65 years, in an 8-week treatment study with 20 mg fluoxetine per day. We recorded for each subject 6 cardiovascular risk factors: age (male ≥45, female ≥55), smoking, family history, hypertension, diabetes, hypercholesterolemia; and we defined a cardiovascular risk score (range, 0–6) by the number of risk factors present. Treatment outcome was measured as response (≥50% improvement on the 17-item Hamilton Rating Scale for Depression [Ham-D-17]) and remission (final Ham-D-17≤7). Results: In logistic regression analyses, the cardiovascular risk score was significantly associated with treatment nonresponse and lack of remission when adjusting for age of onset of MDD and baseline severity of depression. The cardiovascular risk score remained significantly associated with treatment nonresponse when we additionally controlled for overall medical burden (measured with the Cumulative Illness Rating Scale). Among individual cardiovascular risk factors, elevated total cholesterol was a significant predictor of treatment nonresponse and lack of remission. Conclusion: Cardiovascular risk factors may have negative effects on the course of treatment in MDD. These results support the concept of “vascular depression” in younger subjects. MDD = major depressive disorder; Ham-D-17 = the 17-item Hamilton Rating Scale for Depression.