Amritha Bhat

Why has the antidepressant-placebo difference in antidepressant clinical trials diminished over the past three decades?

The increasing rate of failure of antidepressant clinical trials has led to the assertion that antidepressants do not have meaningful clinical benefits. Our hypothesis was that the decrease in antidepressant–placebo differences in antidepressant clinical trials over the past three decades could be explained by changes in research design features rather than a lack of potency of the antidepressants being tested. We collected data from 130 double blind placebo controlled antidepressant clinical trials conducted between 1981 and 2008 that included 35,122 depressed patients with 23,157 patients assigned to antidepressants and 11,965 assigned to placebo. We conducted a hierarchical regression analysis of change in HAM‐D scores in antidepressant and placebo groups separately with year of publication, and research design features as independent variables. We found that antidepressant–placebo differences in antidepressant clinical trials have declined markedly over the past three decades. Decline in change scores in the antidepressant group was related to mean total baseline HAM‐D scores in the trial, the version of HAM‐D used, and duration of trial. Similarly, decline in change scores in the placebo group was related to mean total baseline HAM‐D scores, duration of trial, and year of publication. Overall, we found that antidepressant–placebo differences were statistically significantly higher in trials that used HAM‐D 21 rather than HAM‐D 17 and in trials that lasted 6 weeks or less. These data suggest that, apart from the efficacy of the antidepressant being tested, factors such as baseline HAM‐D scores, version of HAM‐D used and duration of trial have a significant impact on outcome. As such a clinicians assessment of the usefulness of antidepressants should not be based solely on the results of such clinical trials. In the meantime there is a need for continuing research to improve the methodology of antidepressant clinical trials. These data suggest that many aspects of the design of antidepressant trials have a significant impact on outcome. Further, these data suggest that the results of more recent placebo controlled trials do not adequately inform clinicians about the potential utility of antidepressants.

Antidepressant-placebo differences in 16 clinical trials over 10 years at a single site: role of baseline severity

BackgroundAntidepressant–placebo differences observed in randomized double-blind, placebo-controlled clinical trials have always been relatively small and have further declined during the past three decades. During this same time, a decrease in patient severity of symptoms at baseline has occurred. The current study was designed to examine antidepressant–placebo difference scores and baseline severity of depression over a 10-year period in a sample of depressed patients enrolled at a single clinical trial site.MethodsWe analyzed data from a total of 462 patients who participated in 16 clinical trials at the Northwest Clinical Research Center, Bellevue, WA between 1995 and 2004. NWCRC collaborated with study sponsors to unblind the randomization codes from 16 trials for 293 patients assigned to antidepressants and 169 patients assigned to placebo.ResultsThe mean total baseline HAM-D17 scores were relatively high and stable (mean of 24.7, range 22.2–27.4). The outcome, as measured by changes in mean total HAM-D17 scores between antidepressant and placebo, were similar and were not related to the year of the conduct of the trial. Furthermore, the baseline severity of depressive symptoms, and BMI played a significant role in the outcome with antidepressants and not with placebo.ConclusionsOur results show that no diminution of drug–placebo difference occurs over time when baseline severity remains constant. As such, they support the importance of depression severity as a determinant of antidepressant–placebo difference.

Are the colors and shapes of current psychotropics designed to maximize the placebo response

RationalePatient expectations are an important aspect of the placebo response. Color and shape of a medication lead to perceptions that an agent is stimulating or calming, strong or weak.ObjectivesWe assessed the degree to which central nervous system medications match the perceived drug action and thereby harness the placebo response.MethodsWe consulted the 2009 Physicians’ Desk Reference and recorded the formulation and color of each referenced dose of central nervous system therapeutics approved for sale in the USA. On the basis of the expectations they engender, orange, yellow, and red pills were categorized stimulating; green, blue, and purple pills calming. White and gray pills were considered neutral.ResultsThe majority of the 176 unique doses that were included in the study were in tablet (55%) and capsule (33%) form. Stimulants (75%) were the only drug category primarily formulated as capsules. Of the 176 unique doses included, 43% were stimulating, 23% calming, 23% neutral, and 12% were a formulation other than pill or capsule. There were no instances in which over 50% of the pills of an indication were stimulating or calming in color.DiscussionOur study did not confirm the hypothesis that pharmaceutical companies color and formulate the shape of drugs to enhance the treatment response. In several instances, each approved dose of a given medication was a different color, and the majority of doses were in tablet form. Further research into the effect of different colors and formulations of medications on perceptions and efficacy evaluations should be considered.

Infertility and Perinatal Loss: When the Bough Breaks

Infertility and perinatal loss are common, and associated with lower quality of life, marital discord, complicated grief, major depressive disorder, anxiety disorders, and post-traumatic stress disorder. Young women, who lack social supports, have experienced recurrent pregnancy loss or a history of trauma and / or preexisting psychiatric illness are at a higher risk of experiencing psychiatric illnesses or symptoms after a perinatal loss or during infertility. It is especially important to detect, assess, and treat depression, anxiety, or other psychiatric symptoms because infertility or perinatal loss may be caused or perpetuated by such symptoms. Screening, psychoeducation, provision of resources and referrals, and an opportunity to discuss their loss and plan for future pregnancies can facilitate addressing mental health concerns that arise. Women at risk of or who are currently experiencing psychiatric symptoms should receive a comprehensive treatment plan that includes the following: (1) proactive clinical monitoring, (2) evidence-based approaches to psychotherapy, and (3) discussion of risks, benefits, and alternatives of medication treatment during preconception and pregnancy.

Maternal prenatal psychological distress and temperament in 1–4 month old infants – A study in a non-western population

In this longitudinal study, conducted in women attending antenatal visits at the obstetrics and gynecology clinic of a general hospital in Bangalore, India, we aimed to assess the relationship between prenatal distress in mothers, and maternal report of infant temperament at four months. 100 mothers with normal full term deliveries completed the General Health Questionnaire-28 item version (GHQ) in the third trimester and postnatally. Salivary cortisol and temperament (using the Early Infancy Temperament Questionnaire - EITQ) were assessed in their infants aged 1-4 months. In this study, maternal prenatal psychological distress was not significantly associated with maternal report of difficult temperament in infants. Infants of mothers who were a negative screen for psychological distress (GHQ<7), n=85 had higher scores on the adaptability and approach dimensions of temperament. Infant salivary cortisol was significantly higher in infants with higher intensity scores. These results introduce the possibility of cultural differences in the relationship between prenatal distress in the mother and infant temperament. These could be factors linked to child rearing practices or to the measures employed to study infant temperament. These findings derive from a small sample with few mothers with psychological distress, and need replication in a larger sample.

The Obstetrician-Gynecologist's Role in Detecting, Preventing, and Treating Depression.

Women are at a higher risk for depression than are men, and this risk is especially pronounced at specific reproductive periods of vulnerability: adolescence, pregnancy, postpartum, and the menopausal transition. Obstetrician-gynecologists are often the health care providers who women consult during these vulnerable periods, usually presenting with conditions or complaints other than depression or anxiety. Presenting symptoms are frequently known comorbidities with depression or are risk factors for depression. Thus, by screening for depression and other mood disorders in these critical periods, in addition to screening at routine intervals such as annual examinations, obstetricians and gynecologists can play an important role in early detection, prevention, and treatment of mood disorders and their comorbid conditions. We provide a framework for depression management within busy obstetric gynecology settings using new integrated care models for mental health.

Collaborative Care for Perinatal Depression Among Socioeconomically Disadvantaged Women: Adverse Neonatal Birth Events and Treatment Response

OBJECTIVE The study examined the effectiveness of a perinatal collaborative care intervention in moderating the effects of adverse neonatal birth events on risks of postpartum depressive symptoms and impaired functioning among women of lower socioeconomic status with antenatal depression. METHODS A randomized controlled trial with blinded outcome assessments was conducted in ten public health centers, comparing MOMCare (choice of brief interpersonal psychotherapy, pharmacotherapy, or both) with intensive maternity support services (MSS-Plus). Participants had probable diagnoses of major depressive disorder or dysthymia during pregnancy. Generalized estimating equations estimated differences in depression and functioning measures between groups with and without adverse birth events within the treatment arms. A total of 160 women, 43% of whom experienced at least one adverse birth event, were included in the analyses. RESULTS For women who received MOMCare, postpartum depression scores (measured with the Symptom Checklist-20) did not differ by whether or not they experienced an adverse birth event (mean±SD scores of .86±.51 for mothers with an adverse birth event and .83±.56 for mothers with no event; p=.78). For women who received MSS-Plus, having an adverse birth event was associated with persisting depression in the postpartum period (mean scores of 1.20±.0.61 for mothers with an adverse birth event and .93±.52 for mothers without adverse birth event; p=.04). Similar results were seen for depression response rates and functioning. CONCLUSIONS MOMCare mitigated the risk of postpartum depressive symptoms and impaired functioning among women of low socioeconomic status who had antenatal depression and who experienced adverse birth events.

The management of alcohol withdrawal in pregnancy — case report, literature review and preliminary recommendations

Pregnant women are advised to stop drinking alcohol, but there is very little evidence-based guidance on the management of alcohol withdrawal. We describe a case of alcohol withdrawal during pregnancy and summarize available information on treatment.

Text messaging to support a perinatal collaborative care model for depression: A multi-methods inquiry

OBJECTIVE Mental health care integrated into obstetric settings improves access to perinatal depression treatments. Digital interactions such as text messaging between patient and provider can further improve access. We describe the use of text messaging within a perinatal Collaborative Care (CC) program, and explore the association of text messaging content with perinatal depression outcomes. METHODS We analyzed data from an open treatment trial of perinatal CC in a rural obstetric clinic. Twenty five women with Patient Health Questionnaire-9 score of ≥10 enrolled in CC, and used text messaging to communicate with their Care Manager(CM). We used surveys and focus groups to assessacceptability of text messaging with surveys and focus groups. We calculated the number of text messages exchanged, and analyzed content to understand usage patterns. We explored association between text messaging content and depression outcomes. RESULTS CMs initiated 85.4% messages, and patients responded to 86.9% messages. CMs used text messaging for appointment reminders, and patients used it to obtain obstetric and parenting information. CMs had concerns about the likelihood of boundary violations. Patients appreciated the asynchronous nature of text messaging. CONCLUSION Text messaging is feasible and acceptable within a perinatal CC program. We need further research into the effectiveness of text messaging content, and response protocols.

Delivering perinatal depression care in a rural obstetric setting: a mixed methods study of feasibility, acceptability and effectiveness

Abstract Objectives: Universal screening for depression during pregnancy and postpartum is recommended, yet mental health treatment and follow-up rates among screen-positive women in rural settings are low. We studied the feasibility, acceptability and effectiveness of perinatal depression treatment integrated into a rural obstetric setting. Methods: We conducted an open treatment study of a screening and intervention program modified from the Depression Attention for Women Now (DAWN) Collaborative Care model in a rural obstetric clinic. Depression screen-positive pregnant and postpartum women received problem-solving therapy (PST) with or without antidepressants. A care manager coordinated communication between patient, obstetrician and psychiatric consultant. We measured change in the Patient Health Questionnaire 9 (PHQ-9) score. We used surveys and focus groups to measure patient and provider satisfaction and analyzed focus groups using qualitative analysis. Results: The intervention was well accepted by providers and patients, based on survey and focus group data. Feasibility was also evidenced by recruitment (87.1%) and retention (92.6%) rates and depression outcomes (64% with >50% improvement in PHQ 9) which were comparable to clinical trials in similar urban populations. Conclusions for practice: DAWN Collaborative Care modified for treatment of perinatal depression in a rural obstetric setting is feasible and acceptable. Behavioral health services integrated into rural obstetric settings could improve care for perinatal depression.