Combining Antidepressants with ß-Blockers: Evidence of a Clinically Significant CYP2D6 Drug Interaction.

BACKGROUND: The ß-blockers and antidepressants are two of the most commonly prescribed drug classes in the United States. Several antidepressants are potent inhibitors of cytochrome P450 2D6 liver enzymes (CYP2D6) and can increase the plasma concentrations of certain ß-blockers when administered concomitantly, potentially leading to serious medical consequences such as hypotension, bradycardia, and falls. OBJECTIVE: The primary objective of this investigation was to determine whether initiating an antidepressant in patients receiving ß-blockers increased the risk of hemodynamic adverse events. Our primary outcome was time to hospital admissions or emergency department (ED) visits for an International Classification of Diseases-9 diagnosis suggestive of excessive ß-blockade. METHODS: We conducted a survival analysis for adults continuously enrolled in the California Medicaid system (Medi-Cal) between 2004 and 2012. Eligible patients were required to be receiving ß-blocker medications that are primarily CYP2D6 substrates (e.g., metoprolol, propranolol, or carvedilol). Univariate and multivariable analyses were performed for patients who concurrently received antidepressants with ß-blockers. An additional multivariable analysis analyzed the association of this combination upon hospitalizations or ED visits for all causes. RESULTS: A total of 21,292 beneficiaries met the inclusion criteria, and 4.3% of patients required hospitalization or ED visits within 30 days of co-medication. In multivariable analysis, patients receiving antidepressants with moderate to strong CYP2D6 inhibitory potential (fluoxetine, paroxetine, duloxetine, or bupropion) had a greater risk for hospitalization or ED visits for hemodynamic events than those initiated on antidepressants with weak CYP2D6 inhibition for 30 days or less when each was compared with patients receiving no antidepressants (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.03-2.81; p=0.04 vs HR 1.24; 95% CI 0.82-1.88; p=0.30). Other demographic variables associated with increased morbidity included advanced age, male sex, higher ß-blocker doses, and African American race or Hispanic ethnicity. CONCLUSIONS: Results of this analysis suggest that initiation of certain antidepressants was associated with an increased risk for serious medical sequelae among patients concurrently receiving ß-blockers. Greater risk was observed with antidepressants that potently inhibit the CYP2D6 enzyme, implying that increased morbidity may be mediated by a metabolic drug interaction.

Association between Use of Methadone, Other Central Nervous System Depressants, and QTc Interval-Prolonging Medications and Risk of Mortality in a Large Cohort of Women Living with or at Risk for Human Immunodeficiency Virus Infection.

STUDY OBJECTIVE: To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval-prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. DESIGN: Multicenter, prospective, observational cohort study (Women's Interagency HIV Study [WIHS]). PARTICIPANTS: A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. MEASUREMENTS AND MAIN RESULTS: Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994-2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non-acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval-prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.60, p=0.037; HR 1.61, 95% CI 1.35-1.92, p<0.0001; and HR 1.15 per drug, 95% CI 1.00-1.33, p=0.047, respectively. Other explanatory variables for all-cause mortality in this model included HIV viral load, CD4+  cell count, renal function, hemoglobin and albumin levels, HIV treatment era, employment status, existence of depressive symptoms, ever use of injection drugs, and tobacco smoking. Of interest, use of CNS depressants (excluding methadone) was also associated with non-AIDS deaths (HR 1.49, 95% CI 1.49-2.2, p<0.0001). Although use of benzodiazepines and conditional QT interval-prolonging medications were associated with increased risk of non-AIDS mortality (HR 1.32 and 1.25, respectively), the effect was not statistically significant (p>0.05). CONCLUSION: In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval-prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.

Drug Interactions with Lithium: An Update.

Lithium has been used for the management of psychiatric illnesses for over 50 years and it continues to be regarded as a first-line agent for the treatment and prevention of bipolar disorder. Lithium possesses a narrow therapeutic index and comparatively minor alterations in plasma concentrations can have significant clinical sequelae. Several drug classes have been implicated in the development of lithium toxicity over the years, including diuretics and non-steroidal anti-inflammatory compounds, but much of the anecdotal and experimental evidence supporting these interactions is dated, and many newer medications and medication classes have been introduced during the intervening years. This review is intended to provide an update on the accumulated evidence documenting potential interactions with lithium, with a focus on pharmacokinetic insights gained within the last two decades. The clinical relevance and ramifications of these interactions are discussed.

Detection and treatment rates for perinatal depression in a state Medicaid population.

BACKGROUND: The purpose of this investigation was to assess detection and treatment rates for perinatal depression among women enrolled in the California State Medicaid (Medi-Cal) program in comparison to female beneficiaries of reproductive age who did not give birth during the same study period. METHODS: Investigators conducted a retrospective longitudinal cohort analysis of women between the ages of 18 and 39 years old who were continuously enrolled in the Medi-Cal fee-for-service program between January 2006 and December 2009. The perinatal cohort consisted of women with evidence of a live birth occurring between October 2007 and March 2009. The control cohort consisted of women in the same age group and health plan without evidence of pregnancy during this time frame. The primary outcome of this investigation was diagnosis of depression during 3 contiguous 9-month time frames: immediately prior to presumed conception, during pregnancy, and throughout the postpartum period. Secondary outcomes included within-group and cohort comparisons of treatment patterns (antidepressant or psychotherapy). A multivariable analysis of demographic factors predicting depression diagnosis or treatment was conducted as well. RESULTS: A total of 6030 women was identified in the perinatal cohort, and 56,709 women were included in the control group. The perinatal cohort was significantly less likely than nonpregnant controls to receive a diagnosis of depression both during pregnancy (prevalence=1.6% vs 3.5%; OR=0.45; 95% CI=0.35-0.55) and postpartum (2.2% vs 3.6%; OR=0.59; 95% CI=0.50-0.71). Similar differences were noted in antidepressant prescribing patterns apparent during these 2 time frames. A subgroup analysis of women who received a depression diagnosis revealed that only 48% of the perinatal cohort was provided any treatment during pregnancy (vs 72% of the control group; p<0.0001) or postpartum (57% vs 73%; p<0.0001). Specific demographic factors predicting a lower prevalence of depression detection or treatment included Hispanic descent, age <25 years, or primary residence in an rural setting. CONCLUSIONS: Depression was often overlooked and undertreated among women who are pregnant or postpartum in comparison to services delivered to similar nonpregnant controls. Significant disparities in the healthcare received by certain subpopulations of perinatal women suggest that research into barriers to care and subsequent interventions are warranted.

A pilot study evaluating genetic and environmental factors for postpartum depression.

OBJECTIVE: To assess the influence of genetic and environmental risk factors upon postpartum depression. DESIGN: Case-control, prospective study. SETTING: The University of California at San Francisco Obstetric and Gynecology Clinic. PARTICIPANTS: Mothers screened for postpartum depression six weeks after delivery with the Edinburgh Postnatal Depression Scale and recruited as cases and controls. MEASUREMENTS: Eligible subjects completed a series of assessments and a structured clinical interview to confirm diagnosis of depression. Deoxyribonucleic acid was obtained for genotyping of 81 single nucleotide polymorphisms in 12 genes hypothesized to be postpartum depression-related. RESULTS: Twenty-four cases and 24 controls were eligible for analysis. Three single necleotide polymorphisms in the serotonin 2A receptor (HTR2A) gene were associated with postpartum depression. The strongest association at a functional promoter polymorphism (rs6311), a functional promoter single nucleotide polymorphisms (p=0.002, odds ratio 0.25, 95% confidence interval:0.10-0.63), was a finding robust to population stratification. Gene-wide association was significant for HTR2A (permuted p=0.008), but not when corrected for all 12 genes. Analysis of demographic and psychosocial risk factors identified distressed relationship, unplanned pregnancy, and a previous history of depression as significant predictive variables (p≤0.05). CONCLUSIONS: This pilot data suggests deoxyribonucleic acid variations in HTR2A may be associated with postpartum depression. Psychosocial variables were also identified as risk factors. The relative influence of these variables on the manifestation of postpartum depression is yet to be determined.

Clinical and economic outcomes of a pilot project examining pharmacist-focused collaborative care treatment for depression.

OBJECTIVE: To assess the clinical and economic impact of a pharmacist-focused health management program for patients with depression. DESIGN: Prospective, nonrandomized, proof-of-concept investigation. SETTING: Asheville, NC, from July 2006 through December 2007. PARTICIPANTS: Employees or adult dependents with depressive symptoms who agreed to enroll in an employer-sponsored treatment program conducted at two ambulatory clinics where consultative services were provided. Participants were included in the analysis if they participated in the program for at least 1 year and had two or more documented visits with a pharmacist. INTERVENTION: Outpatient-based pharmacists provided assessment, self-management services follow-up, and treatment recommendations to primary care providers within a collaborative care management model. MAIN OUTCOME MEASURES: Changes in severity of depressive symptoms and impact on overall health care costs for employers and beneficiaries. RESULTS: Of the 151 beneficiaries referred to the program, 130 (82%) remained under pharmacist care for a minimum of 1 year and were included in the aggregate analysis. Statistically significant improvements were observed for Patient Health Questionnaire (PHQ)-9 scores from baseline to endpoint (11.5 ± 6.6 to 5.3 ± 4.7 [mean ± SD], P < 0.0001). The clinical response rate was 68% with a 56% remission rate. In economic subgroup analysis (n = 48), annual medical costs decreased from an average of $6,351 per enrollee to $5,876, which was lower than the projected value ($7,195). Total health care costs to the employer increased from $7,935 per enrollee to $8,040, which was lower than the projected value ($9,023). CONCLUSION: Patients in the first year of the program had significant improvement in the PHQ-9 clinical indicator of depression severity. Total health care costs per patient per year were reduced compared with projected costs without the program. Employers expressed their appreciation for this collaborative care program and continued to offer this voluntary health benefit after the study's conclusion.

Pharmacologic treatment for postpartum depression: a systematic review.

During the past decade, the medical community has expressed a growing concern over the high prevalence of postpartum depression and the tragic repercussions of untreated illness. However, many questions persist about the pathogenesis of postpartum depression, the natural course of the illness, and the safety and effectiveness of available treatments. To summarize the data on pharmacologic treatments for postpartum depression, we performed a systematic review of four major databases to identify original research published from 1960-September 2009 that featured pharmacologic treatments for depression detected in women during the 12 months after delivery. Pharmacologic treatments included prescription drugs (antidepressants and hormones), herbal remedies, and dietary supplements. Case reports, studies examining the prevention of postpartum depression, and those including diagnosed episodes of depression preceding the postpartum period (i.e., antepartum onset) were excluded. Treatment randomization or the presence of a control group was not required for inclusion in this review. Fourteen investigations met inclusion criteria. Nine studies examined the effects of prescription antidepressants, two investigated hormones, and three featured omega-3 fatty acid supplementation. Significant heterogeneity was evident in study design and prevented a pooled quantitative analysis of treatment effects. The power of most investigations was limited, and numerous confounding biases were evident. Therapeutic effects were documented for prescription antidepressants and hormone supplementation (estrogen derivatives). Tolerability of the interventions in depressed mothers and breastfed infants was not well described. The effectiveness of omega-3 fatty acids was not evident in postpartum depression trials, although significant limitations in study methodology were apparent. Postpartum depression is a common and serious medical problem, but most cases go undetected and untreated. The need to identify safe, effective, and convenient treatments for postpartum depression is urgent, but the current state of the medical literature describing pharmacologic interventions is not impressive. Preliminary evidence documenting the effectiveness of serotonergic antidepressants and hormone supplementation should serve as an impetus for rigorous controlled investigations in the future.

Heart of Pharmacy: a course exploring the psychosocial issues of patient care.

OBJECTIVE: To implement and assess the impact of a course utilizing reflective learning to explore the complex, psychosocial human issues encountered in pharmacy practice. DESIGN: A 1-credit-hour elective course, The Heart of Pharmacy, was offered to all pharmacy students. The course utilized both content and reflective techniques to produce a mutual exploratory learning experience for students, staff, and faculty members. Faculty and staff facilitators observed competencies and used a single group posttest design to assess students' attitudes. In year four, students' written reflections for each session were added and reviewed on a continuous basis throughout the course. ASSESSMENT: Faculty and staff observations indicated that educational outcomes were achieved and student perceptions and evaluations of the course were highly positive. Three major themes were identified in the students' qualitative responses: a recognition of communal support among student and faculty colleagues; a grounding for personal growth and professional formation; a deeper insight into and experience with the role of the pharmacist as compassionate listener and caregiver. CONCLUSION: Faculty observations of student competencies and students' perceptions of this course point to the need for pharmacy education to provide organized, structured reflective learning opportunities for students and faculty members to explore the deeper human issues of pharmacy practice and patient care.

Tamoxifen treatment and new-onset depression in breast cancer patients.

The authors conducted a retrospective cohort study of female patients diagnosed with breast cancer (BRCA), evaluating the risk of new-onset depression associated with tamoxifen treatment among those with estrogen receptor-positive (ER+) tumors, versus estrogen receptor-negative (ER-) tumors, who were not receiving tamoxifen. A total cohort of 2,943 patients was identified. The hazard-ratio for new-onset depression in the tamoxifen group was nonsignificant. A post-hoc analysis revealed that chemotherapy and ER+ status were significantly and independently associated with an increased risk for developing depression.

Evaluating the impact of pharmacists in mental health: a systematic review.

Efforts to improve the outcomes of patients with mental illness often have involved incorporating the skills of a variety of health care professionals into collaborative care models. For over 30 years, clinical pharmacists have contributed to these care models in capacities ranging from educator to consultant to provider. This systematic review evaluates the quantity and quality of medical literature examining the impact of pharmacists in mental health from 1972-2003. Although we identified approximately 35 publications describing the roles of clinical pharmacists in this regard, only 16 were of sufficient scientific rigor to permit evaluation and comparison. The 16 studies were divided equally between inpatient and outpatient settings and were conducted in a variety of health care organizations (e.g., Veterans Administration, health maintenance organizations, community mental health clinics, and nursing homes). Nine of the studies examined the role of pharmacists in providing treatment recommendations and patient education, five featured pharmacists as providers (with prescriptive authority), and the remaining two described the impact pharmacists have in delivering education to the psychiatric staff. Six of the 16 studies were prospective, but only three of these incorporated a randomization procedure for patients or facilities. Collectively, the results of the 16 studies were positive, demonstrating improvements in outcomes, prescribing practices, patient satisfaction, and resource use. Unfortunately, most of the investigations were small, and significant limitations in study design limited further comparison. Given the long history and anecdotal success of pharmacists in mental health care settings, additional multicenter cost-effectiveness trials are warranted to further support the role of the psychiatric pharmacist.

Impact of a collaborative care model on depression in a primary care setting: a randomized controlled trial.

To measure the effects of a collaborative care model that emphasized the role of clinical pharmacists in providing drug therapy management and treatment follow-up to patients with depression, we conducted a randomized controlled trial at a staff model health maintenance organization. We compared the outcomes of subjects treated in this collaborative care model (75 patients, intervention group) with subjects receiving usual care (50 patients, control group). After 6 months, the intervention group demonstrated a significantly higher drug adherence rate than that of the control group (67% vs 48%, odds ratio 2.17, 95% confidence interval 1.04-4.51, p=0.038). Patient satisfaction was significantly greater among members randomly assigned to pharmacists' services than among controls, and provider satisfaction surveys revealed high approval rates as well. Changes in resource utilization were favorable for the intervention group, but differences from the control group did not achieve statistical significance. Clinical improvement was noted in both groups, but the difference was not significant. Clinical pharmacists had a favorable effect on multiple aspects of patient care. Future studies of this model in other health care settings appear warranted.

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings.

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.

Impact of a collaborative pharmacy practice model on the treatment of depression in primary care.

The effects of a collaborative pharmacy practice model, in which clinical pharmacy specialists provided medication maintenance and follow-up patient care services at a clinic, on patients' adherence to treatment and satisfaction and costs were studied. A cohort of 13 primary care providers (PCPs) was designated to refer patients diagnosed with depression to the practice model at a staff-model health maintenance organization (HMO) immediately after the initiation of antidepressant medications. Clinical pharmacy specialists proceeded to coordinate follow-up with the patients for six months through a combination of scheduled office visits and telephone calls. Working closely with psychiatric liaisons, pharmacists were granted limited prescribing privileges to provide medication comanagement. These patients' adherence to treatment and satisfaction and costs to the HMO were compared with a control group of patients being treated for depression by the remaining 17 PCPs at the facility. A total of 91 patients were referred to the intervention group and received care from the pharmacists during the 10-month enrollment phase; 129 patients were included in the control group. There were no significant differences between groups regarding age, sex and chronic disease scores. An intent-to-treat analysis of medication adherence revealed that adherence was significantly higher in the intervention group (medication possession ratio, 0.81 versus 0.66) (p = 0.0005). Medication switch rates were higher among intervention patients as well (24% versus 5%) (p = 0.0001). There was a greater decline in the number of visits to PCPs for patients in the intervention group (39% versus 12%) (p = 0.029). A collaborative practice model in which clinical pharmacy specialists managed the medication therapy of patients with mild to moderate depression increased patients' adherence to treatment and their satisfaction and reduced the patients' subsequent visits to PCPs.

Clinical and economic outcomes associated with olanzapine for the treatment of psychotic symptoms in a county mental health population.

BACKGROUND: The comparatively high acquisition costs of the newer antipsychotic medications have caused the mental health community to look closely at their potential benefits. OBJECTIVE: The purpose of this study was to perform a naturalistic analysis of changes in mental health service utilization, economic costs, and clinical outcomes after the initiation of olanzapine therapy for psychotic symptoms in an indigent patient population from a large county-operated mental health care system. METHODS: This was a prospective, uncontrolled investigation using a mirror-image cohort design. All captured costs from patients who began olanzapine therapy between November 1, 1996, and April 30, 1998, were analyzed in an intent-to-treat fashion to compare resource utilization in the 12 months immediately before and after the intervention. Clinical function was assessed at baseline and 6 months using the Positive and Negative Syndrome Scale (PANSS). In a subgroup analysis, the baseline characteristics of patients who completed 12 months of olanzapine treatment were compared with those of patients who (1) changed medication or (2) changed pay or source or were lost to follow-up. RESULTS: One hundred eighty-nine patients were started on olanzapine treatment during the 18-month study entry phase. Patients were primarily male (63.5%) and had a mean age of 35.9 years. Most (66.3%) had a formal diagnosis of thought disorder. Fifty-six patients received olanzapine for 12 consecutive months, and 22 were switched to other psychotropic medications. Of the remaining 111 patients, 70 changed payors (ie, qualified for Medicaid), and 41 were lost to follow-up. In the subgroup analysis, patients who completed 12 months of treatment (ie, responders) had significantly lower mean PANSS total scores at baseline compared with those who changed payors or were lost to follow-up (P = 0.047), and were significantly more likely to have a formal diagnosis of thought disorder (P = 0.039). Responders demonstrated a significant reduction in PANSS total and negative subscale scores at 6-month follow-up (both measures, P < 0.001). In the intent-to-treat analysis of resource utilization in all patients with complete data sets (n = 78), hospitalization costs and crisis costs decreased significantly during the 12-month follow-up period (P = 0.003 and P = 0.009, respectively), and both outpatient and medication costs increased significantly (P = 0.035 and P < 0.001, respectively). Overall, the change in total annual resource utilization during the 12 months after initiation of olanzapine was not statistically significant (mean decrease per patient, $1,991; 95% CI, -$5,258 to $1,122). CONCLUSIONS: Initiation of olanzapine therapy was associated with favorable clinical outcomes in this population, particularly in patients with a formal diagnosis of thought disorder. Overall, there was a cost shift away from hospital and crisis costs toward medication and outpatient services costs. The decline in total resource utilization was not statistically significant, although it may be of practical importance.