Journal of Affective Disorders 117 (2009) 18–23

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Journal of Affective Disorders

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Research report

Polypharmacy prevalence rates in the treatment of unipolar depression in anoutpatient clinic

Anna Glezer a,⁎, Nancy Byatt b, Richard Cook Jr. b, Anthony J. Rothschild b,c

a Massachusetts General Hospital/McLean Hospital Psychiatry Residency Training Program; University of Massachusetts Medical School. 15 Parkman Street,Wang 812 Boston, MA 02114, United Statesb University of Massachusetts Medical School; UMass Memorial Health Care, United Statesc University of Massachusetts Medical School, 361 Plantation St., Worcester, Massachusetts, 01605, United States

a r t i c l e i n f o

⁎ Corresponding author. Tel.: +1 617 724 6300 #13E-mail addresses: Aglezer@partners.org (A. Glezer

(N. Byatt), Rothscha@ummhc.org (A.J. Rothschild).

0165-0327/$ – see front matter © 2008 Elsevier B.V.doi:10.1016/j.jad.2008.11.016

a b s t r a c t

Article history:Received 26 November 2007Received in revised form 16 November 2008Accepted 18 November 2008Available online 21 December 2008

Objective: Unipolar depression is a complex illness with an ever increasing number ofpharmacological treatments available. As the number of available medication options increases,sodoes thepotential for polypharmacy, a practicewith possible complications. Such complicationsinclude a greater number of side effects with the initiation of additional medications and theconsequences of drug–drug interactions. Therefore, it is important to understand the effects ofpolypharmacy on efficacy of treatment as well as whether polypharmacy is instituted afterappropriate initial monotherapy trials. This study attempts to answer these questions.

Methods: Patient names for this investigationwere provided by residents in the UMass MedicalSchool Psychiatry Residency program. The charts of these patients were analyzed to collect dataregarding demographics, clinical data about the illness, medication names, types, duration ofuse and to access efficacy using the Clinical Global Impression (CGI).

Results: Of 160 reviewed charts,135 subjects were included in the final analyses (others excludeddue to incomplete data or no depression diagnosis). Patients were on average on 2.0 medications(SD=0.5) with 2.1 past trials. A greater number of current antidepressant medications did notcorrelatewith a greater improvement in CGI, implying that polypharmacy did not necessarily leadto greater efficacy. The impact of illness severity, as measured by comorbidities, substance abuse,and trauma history, were included in the analysis, and did not significantly change this outcome.Additionally, prescription patterns themselves were examined, including reasons for terminationof medication trials, the impact of side-effects, and the number of patients that had completemonotherapy trials before transitioning to polypharmacy.

Study limitations: Small sample size, retrospective review, one CGI rater.

Conclusions: First, many patients did not receive an adequate monotherapy trial, as defined bydose and duration, before progressing to polypharmacy. Secondly, the use of two or moremedications concurrently did not appear to increase efficacy as measured by CGI. Due to studylimitations, direct comparison of the efficacy of one and two medications was not significant;however the study did demonstrate a general correlation between polypharmacy and greaterdepressive symptomatology. This suggests the need for optimizing monotherapy regimensbefore initiating polypharmacy that may not lead to improvement in symptoms.

© 2008 Elsevier B.V. All rights reserved.

Keywords:PsychopharmacologyPolypharmacyDepressionTreatment

4 0350.), Nbyatt@verizon.net

All rights reserved.

1. Introduction

Major Depressive Disorder is a complex psychiatric illnessaffecting 15–20% of the American population. Treatmentoften entails a combination of psychopharmacologic andpsychotherapeutic interventions. In recent years, the number

19A. Glezer et al. / Journal of Affective Disorders 117 (2009) 18–23

of psychotropic medications available for the treatment ofdepression has significantly increased, providing more treat-ment options for patients.

With the development of psychopharmacologic treat-ments for Major Depression, a new trend may be emerging:increased polypharmacy – the use of multiple psychiatricmedications concurrently – for the treatment of depression.One investigation looking at prevalence rates over the pastdecades found that the percentage of patients with adiagnosed mood disorder discharged from the NIMH hospitalon three or more medications was 3.3% in 1974–1979, then9.3% in 1980–1984, rising to 34.9% in 1985–1989, and jumpingto 43.8% in the period of 1990–1994 (Frye et al., 2000).

Most clinicianswouldassert that thepurposeofpolypharmacyis to increaseefficacy, andother reasons, includingmanagementofside effects or treating co-morbid conditions. The link, however,betweenpolypharmacyandefficacyhasnotbeenwell established.A goal of this study was to assess this relationship betweenincreased number of antidepressant medications used concur-rently and successful reduction of depressive symptoms.

This question has been studied in inpatient facilities(Barbui et al., 2005) and international settings (Centorrinoet al., 2002), and by examining antipsychotic medications(Ganguly et al., 2004; Janseen et al., 2004). This investigationfocuses on patients diagnosed with unipolar depression at anoutpatient clinic, as this environment and patient populationhas not previously been targeted. The out-patient clinicchosen was a resident-run clinic. Analysis of residentprescribing practices may speak to the current training theyare receiving, whether polypharmacy practices are beingperpetuated in the next generation of psychiatrists.

Several potential complicating factors may contribute topolypharmacy. A longer duration of a major depressiveepisode or illness complicated by comorbid diagnoses maynecessitate the use of multiple medications. These confound-ing factors were addressed in the development of this study.The effects of an abuse history, substance abuse, and age ofillness onset were also examined asmarkers of severity. Otherkey contributors to polypharmacy, such as side-effect man-agement, previous medication failure or inadequate responseare also important, but are not directly addressed by thisinvestigation, and this is noted under “limitations”.

A second goal of this investigation was to determinewhether polypharmacy was being utilized after exhaustion ofmonotherapy options. Several algorithms exist (Osser, 1996–2003; TMAP, 2007) making recommendations regardingpsychotropic medication therapy initiation and progression.These guidelines (and others such as those created by the APA)currently recommend starting with an SSRI to treat unipolardepression (Simon, 2001). These medications are effective forsymptom reduction while having one of the lowest side-effectprofiles of currently available anti-depressants and little abuseor overdose potential. One major recent investigation addres-sing this issue has been the STAR⁎D (Rush et al., 2006) trial,which demonstrated almost one third remission using mono-therapy (citalopram), and emphasized the need for longer trialsbefore changing treatment.

Several potential downfalls exist in using complex medica-tion regimens in the treatment of depression. Increasing healthcare costs and the expense of psychotropic medications(Kendrick et al., 2006; Nurnberg et al.,1999)may be prohibitive

to some patients and drive up costs in general. Additionally, ithas been shown that as the number of prescribed medicationsincreases, patient compliance decreases (Haynes,1976). Addingmultiple medications may also increase the number of sideeffects a patient experiences and lead to potentially dangerousdrug–drug interactions. These factors, in turn, may engender aworse outcome in the treatment of this illness.

1.1. Methodology

Approval for the chart review studywas obtained from theUniversity of Massachusetts Medical School InstitutionalReview Board. Names of patients were provided by all thirdand fourth year residents in the University of MassachusettsMedical School Psychiatry Residency Program. A total of 169names were provided by residents, having been asked for listsof current outpatients with diagnosis of unipolar depression.Charts were reviewed via the electronic medical record andpaper documents. After review, 126 patients were includedfor analysis. Subjects were excluded if they did not have adiagnosis of unipolar depression, or if there were no recordsof follow-up visits after the initial intake.

Each chart was assessed for demographic information –

patient age, race, and gender – and to confirm diagnosis. Thecurrent or most recent Major Depressive Episode wasreviewed to determine which medications the patient wastaking and for what duration. Efficacy was assessed using theClinical Global Impression Scale (CGI). Initial CGI datareflected illness severity at the start of the current episodeand thefinal CGI reflected change byOctober, 2006 (when thisreviewwas conducted) or resolution of episode and symptomremission, whichever came first. Resolution and symptomremission were determined by either empiric data (ie. ratingscales) or by the use of terms “in remission” found in progressnotes. All CGI ratings were done by the first author.

Informationwas gathered regarding past medication trialsand side-effects experienced. The Antidepressant TreatmentHistory Form (Oquendo et al., 2003) was used to documentwhether a medication trial was complete (ie. fluoxetine at40 mg for 6 wks) or incomplete (ie. fluoxetine at any dose forless than 4weeks). The ATHF takes into account both durationand dose. Medications were classified as antidepressants (ie.SSRIs, TCAs, mirtazepine, buproprion) or general psychotro-pics (antipsychotics, benzodiazepines, sleep aids).

Finally, the number of current psychiatric diagnoses,substance abuse history, and a history of physical or sexualabuse were all noted if that information was available in thecharts. The addition of psychotherapy to treatment regimenswas not included in the review.

Statistics were performed using Excel and SPSS software.Pearson correlations and linear regression were conducted todetermine correlations among various ordinal and contin-uous factors. A statistical significance level of 0.05 was used.

2. Results

2.1. Patient descriptives

Patients included in this study were on average 45.6 yearsold (SD 13.9), with slightlymorewomen thanmen (73 vs. 53).The populationwas predominantly Caucasian (N=104, 83%).

Fig. 2. Statistically significant positive Pearson correlation (p=0.009)between the number of antidepressant medications a patient is taking andthe final CGI score. ANOVA significant at p=0.013. Post-hoc analysis did notdemonstrate significant differences between none, one, and twomedications.

20 A. Glezer et al. / Journal of Affective Disorders 117 (2009) 18–23

2.2. Illness descriptives

The average duration of the current or most recent MajorDepressive Episode was 1.90 years (SD 2.10), ranging 0.08–16.0. The most common age of illness onset was 20–40 yrs(40%, N=48), followed closely by diagnosis before age 20(38%, N=46). Nineteen percent (N=27) were diagnosed inmiddle age (40–60 yrs.) and rarely (3%, N=4) were subjectsdiagnosed with depression after age 60.

The majority of patients had diagnoses of unipolardepression without psychosis; 16 had MDD with psychosis.Fifty percent (N=62) had current or past histories ofsubstance abuse and more than half of those for whominformation was available regarding physical or sexual abusedisclosed having been abused (54%, N=55). The majority ofpatients had at least one comorbid diagnosis – commonly ananxiety disorder. The mean CGI score at baseline was 4.26±0.96, which corresponds to a “moderate” severity of illness.

2.3. Treatment impact

Overall, there was an improvement in depressive symp-toms with treatment. The average final CGI score was 2.56±1.16, which is in the “improved” range, with 76% (N=96) ofpatients reporting improvement in depression symptomatol-ogy. More specifically, 20% (N=25) achieved symptomremission, defined by a CGI score of 1, 33% (N=42)demonstrated marked improvement (CGI=2), and 23%(N=29) showed minor improvement (CGI=3). Twentypercent (N=25) of all patients did not show any change inCGI score. Three percent (4 patients) did show minorworsening (CGI=5), and 0.8% (1 patient) had significantlyworse symptoms (CGI=6). The amount of improvement, orfinal CGI score, was independent of the initial severity, thestarting CGI score.

2.4. Impact of illness severity

T-tests determined no statistically significant difference inthe final CGI score between patients with and withoutsubstance abuse (p=0.09). There was also no differencebetween those who reported and those who denied a historyof abuse (p=0.26). Mean final CGI scores did not significantlydiffer between those with MDD with psychosis and thosewithout psychosis (p=0.06).

The majority of subjects had one or more comorbiddiagnoses (78%). The mean final CGI score comparing those

Fig. 1. Statistically significant positive Pearson correlation (0.28) between thenumber of total psychotropic medications a patient is taking and the final CGscore p=0.036, implying that greater number of medications is associatedwith worse outcomes. ANOVA not statistically significant p=0.181.

Fig. 3. Positive Pearson correlation coefficient (0.15) between the number ofantidepressant medications at full trial dosing a patient is taking and the finalCGI score. ANOVA significant at p=0.019. Post-hoc analysis did notdemonstrate significant differences between none, one, and twomedications.

I

with and without comorbid diagnoses did differ (one-wayANOVA p=0.035). Patients with two or more comorbiddiagnoses had significantly higher mean final CGI scores(2.92±1.14) when compared with patients without anycomorbid diagnosis (2.31±1.15) (p=0.04).

There was no significant correlation between the age ofillness onset and the starting CGI, the marker of illnessseverity (p=0.50). No statistically significant relationshipwas noted between baseline CGI scores and final CGI scores(p=0.24), implying that the severity at the start of thedepressive episode did not impact the final outcomes.

2.5. Medication impact

Medication regimens were assessed based on totalnumber of psychotropic medications a patient was taking,the number of antidepressantmedications, and the number ofantidepressant medications at full dose, as defined by theATHF. Patients were prescribed a mean of 1.98 (SD 0.94)psychotropic medications, 1.15 (SD 0.52) antidepressants, and0.64 (SD 0.59) full dosed antidepressants. Fifty-six percent(N=70) of patients were on one full dose of an antidepres-sant medication. Forty percent (N=51) did not have a fulldose of any antidepressant medication.

21A. Glezer et al. / Journal of Affective Disorders 117 (2009) 18–23

There was a statistically significant positive correlation(p=0.028) between the number of total medications apatient was taking and the final CGI, and a statisticallysignificant positive correlation (p=0.009) between thenumber of antidepressant medications and a higher finalCGI score. There was no statistically significant correlationbetween number of antidepressants at full dose a patient wasprescribed and the final CGI, but the correlation trendedpositively (correlation coefficient=0.15).

No relationship existed between total number of psycho-tropic medications and final CGI score (ANOVA p=0.181)Fig. 1. However, there was a statistically significant associationbetween the final CGI score and total number of antidepres-sant therapies (ANOVA p=0.013) (Fig. 2). There also was astatistically significant association between the final CGI scoreand the total number of full-trial antidepressant therapies(ANOVA=0.019) (Fig. 3).

The relationship between illness severity, as measured bystarting CGI score, and the number of current and pastmedication trialswas analyzed.While therewas no significantrelationship between starting CGI and the number of currentantidepressantmedications prescribed (p=0.48), therewas ahighly significant correlation between the starting CGI andboth the number of full dose antidepressant medications apatient was currently prescribed (p=0.004) and the totalnumber of psychotropic medications a patient was currentlyprescribed (pb0.001). There were no relationships betweenstarting CGI scores and number of pastmedication trials of fulldose or incomplete dose antidepressants.

Furthermore, the presence of psychosis in the diagnosisdid significantly correlate with an increased total number ofactive psychotropicmedications (p=0.024), explained the bythe addition of an antipsychotic medication to the regimen.An increased number of comorbid diagnoses was alsosignificantly correlated with a higher number of pastantidepressant complete trials (p=0.041).

The number of comorbid diagnoses did not impact thefinal CGI score. When controlling for the number of comorbiddiagnoses, there remained a significant positive correlationbetween the final CGI score and both the number ofprescribed antidepressants (p=0.009) and the total numberof psychotropicmedications (p=0.036). This implies that theprior finding of a worse outcome with greater numbers ofmedications is not explained by the presumption thatpatients with more comorbid diagnoses, a marker of severity,are prescribed more medications.

Lastly, medication prescription patterns themselves wereassessed, such as number of complete or incomplete trials, theuse of SSRIs versus other antidepressants, and the impact ofside effects on medication use. The mean number ofincomplete or unknown trials reported was 1.71 (SD 1.65),ranging from 0–7, with 74% (N=88) of patients having one ormore incomplete trials of antidepressant medications or trialswithout known outcomes. However, 33% of patients (N=44)had had at least one complete past medication trial (adequatedose and duration). Nineteen percent of patients (N=24) inthis study had no previous medication trials. Additionally,patients had an average of 2.17 (SD 1.16) trials (complete orincomplete) of an SSRI/SNRI medication and 1.21 (SD 1.29)trials of other antidepressant medications. Only 2 patients didnot have any past or active trials of an SSRI/SNRI medication.

Data was collected regarding number of antidepressantmedication trials stopped due to side effects. Almost 40%(N=50) of subjects had a history of discontinuing one ormore medications secondary to side-effects. Of those that didterminate a trial, 62% (N=31) had one truncated medicationtrial due to side-effects, 16% (N=8) had discontinued twotrials, and 22% (N=11) had stopped three or more medica-tion trials. Overall, 215 past trials of medications werediscontinued without a known complete trial, and 88 (41%)total trials were discontinued secondary to side-effects. Whilethe final outcome as measured by CGI did not correlate withnumber of medications discontinued in the past due to side-effects (p=0.59), an increased number of trials terminateddue to side-effects did significantly correlate with anincreased number of past medication trials (pb0.001).Clearly, an increased number of side-effects may lead togreater frequency of premature medication trial discontinua-tion, thereby increasing the numbers of incomplete medica-tion trials. However, there was insufficient data to determinewhether side-effects were more likely to be experienced asthe number of concurrent psychotropic medications pre-scribed increased.

3. Discussion

Rates of polypharmacy prescription in the treatment ofdepression have been increasing. This study was conducted toelucidate the pattern of transition from first line treatments topolypharmacy and to evaluate the relationship between theuse of multiple concurrent psychotropic medications andtreatment efficacy.

The first main goal of the investigation – to addressprescribing patterns – was attained. The hope was todetermine if patients are undergoing trials of first-linetherapies like SSRIs before progressing to more complexregimens. In this study sample, the majority of patients (98%)had undergone a trial of an SSRI/SNRI, which is encouragingas these medications are often recommended as first-linechoices. On the other hand, almost three quarters of patients(74%) had experienced at least one incomplete trial or onewithout a known outcome. More startling was that almosthalf (40%) of patients did not receive a full dose of anymedication. Coupled with these results was that patientswere, on average, prescribed two (mean=1.98) psychotropicmedications and more than one (mean=1.15) antidepres-sant. This suggests that patients had medications added totheir regimen without optimizing the initial treatments,leading to polypharmacy. While possible that some patientswere started on augmentation therapies to boost response, asreported to be efficacious in other clinical trials like STAR⁎D(Trivedi et al., 2006), these strategies are recommended afterexhaustion of monotherapy.

The experience of side-effects is a common reason forterminating a medication trial. However, less than half of allincomplete trials (41%) were those stopped secondary toside-effects. Other reasons for premature trial cessationincluded self-discontinuation by the patient due to cost,lack of desire to continue medication, or running out of refills.Oftentimes, the reason was unknown or the data unavailable.

Additionally, the data suggest a relationship betweentreatment outcome and number of prescribed medications.

22 A. Glezer et al. / Journal of Affective Disorders 117 (2009) 18–23

There was a significant correlation between a worse treat-ment outcome (as defined by the CGI score) and both the totalnumber of psychotropic medications and the number ofantidepressants. This may be evidence that polypharmacydoes not improve clinical outcomes. One question introducedwith such investigations is how to distinguish betweenpatient severity and polypharmacy as both affect treatmentresponse. That is, patients prescribed more medications mayinherently have a more complicated course of illness, therebyexplaining the worse outcome. This study attempted toaddress this issue by isolating certain features of clinicalillness that lead to a more severe picture. A history ofsubstance abuse, physical or sexual abuse, and presence ofpsychosis were not associated with worse outcomes. Norwere these factors associated with greater numbers ofprescribed medications – except that a diagnosis of MDDwith psychosis correlated with greater number of totalpsychotropic medications. Controlling for the presence ofcomorbid diagnoses led to similar conclusions, namely thatworse outcomes were associated with greater numbers ofantidepressants and psychotropic medications in general. Ithas been suggested by prior investigations that patientssuffering from treatment resistant depression benefit frompolypharmacy prescription at the outset. However, this wasnot the targeted population in this study. One potential futuredirection for investigation is delving more deeply intotreatment resistant depression and how other measures ofseverity impact treatment outcome and the use of multiplemedications.

3.1. Study limitations

Several methodological shortcomings limit this investiga-tion. First, thiswas a retrospective chart reviewwith a relativelysmall N, making it less ideal for deciphering the roots behindthe relationship betweenpolypharmacyand treatment efficacy,although valid to describe medication prescription patterns.Additionally, only one rater was used to gauge CGI, whichpromotes consistency, but cannot speak to inter-rater reliabilityof the scores. Finally, several confounds were addressed tobetter elucidate the relationship between polypharmacy andtreatment efficacy, such as the presence of psychosis, substanceabuse, and trauma history. However, this information was notpresent on every patient, and other confounding factors mayexist that could be addressed in future investigations, such asadditional medical or psychiatric co-morbidities. The impact ofpsychotherapy was not dealt with in this study, and can beanother avenue of future investigation.

4. Conclusions

The increasingly common practice of polypharmacy fortreatment of mental illness is concerning given the potentialincreased risk of side-effects, decreased compliance, andincreased costs. This investigation demonstrated that patientsoften receive incomplete trials of medication before advan-cing to more complicated regimens. Additionally, greaternumbers of antidepressants and psychotropic medications ingeneral are not necessarily correlated with improved out-comes in the outpatient treatment of unipolar depression.What requires further investigation is whether there is any

advantage to polypharmacy in the treatment of unipolardepression versus an adequate monotherapy trial of adifferent FDA-approved medication. Until those studies areconducted, the results of this investigation should promptclinicians to assess their prescribing patterns and evaluate themedication regimens of patients on polypharmacy and thosewhose monotherapy regimens may be suboptimal.

Role of funding sourcesThere was no funding provided for this research as it was primarily done

during the primary investigator's time in medical school.

Conflicts of interest and author disclosuresDr. Anthony J. Rothschild has received research support from NIMH,

Wyeth, Novartis, and Cyberonics; served as a consultant to Pfizer, Glaxo,Forest, and Lilly; and has received honoraria and served on the speakersbureaus of Bristol-Myers, Lilly, Pfizer, and Forest.

Drs. Anna Glezer, Nancy Byatt, and Richard Cook do not have anydisclosures.

Acknowledgements

The authors of this research paper would like to acknowl-edge the support staff of the Center for PsychopharmacologicResearch and Treatment at the University of MassachusettsMedical School as well as those involved in the SeniorScholars Research Program at the University of MassachusettsMedical School. We would also like to thank the residents ofthe Psychiatry Training Programwho provided patient namesand data for this project.

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