This study aimed to investigate antidepressant prescribing patterns, including initial choice, switching and combining, and concomitant use of non-antidepressant agents, for depressive disorders in naturalistic clinical care settings in Korea.
Patients with depressive disorder were recruited from both outpatient and inpatient settings in 18 hospitals from all over Korea. Treatment was performed in naturalistic patterns based on each clinician's decision. Data were collected on the prescription of antidepressants and concomitant agents from baseline to 12-week follow-up.
Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed initial antidepressant (48.9%), followed by newer dual-action antidepressants (45.8%). When an SSRI was the initial antidepressant, 46.2% of patients whose medication was changed were moved to newer dual-action antidepressants, and 67.4% of combination cases were combined with newer dual-action ones. When a newer dual-action antidepressant was the initial antidepressant, 70.6% of patients whose medication was changed were moved to SSRIs, and other antidepressants including tricyclic antidepressants were most commonly added for combination treatment (50% of combination cases). During the treatment period, 20.6% of antidepressants prescribed were augmented by non-antidepressant agents, and 75.1% were used concomitantly with anxiolytics or hypnotics. The most commonly used concomitant non-antidepressant agent was quetiapine.
The selection of antidepressants and the concomitant use of non-antidepressant agents are becoming increasingly diversified, and the results of this study reflect changes in the prescribing pattern in actual Korean practices.
Depressive disorders are highly prevalent throughout the world.
To enhance treatment success rates, the most appropriate antidepressants should be selected according to symptoms and patient characteristics. Many factors have been reported to influence the choice of antidepressant prescribed by clinicians, including the severity of depression, previous depressive episodes, the presence of comorbid conditions, and previous use of antidepressants.
Increasing numbers and types of antidepressant are now available in the Korean marketplace, so the armamentarium of antidepressant medications has expanded considerably. However, little is known about current prescribing practices in Korea in the treatment of depressive disorders. Most previous studies on antidepressant prescription practices in Korea have been in the form of survey research; although such studies might reflect preferred treatment strategies, they do not show real prescription patterns in actual clinical settings. To the best of our knowledge, there has been no nationwide prospective study on prescription patterns in the treatment of depressive disorders in actual practice settings in Korea.
The Clinical Research Center for Depression (CRESCEND) study is the first long-term prospective clinical study on depression in Korea, with a large nationwide sample population and government support. It is a naturalistic study in real-world practice settings investigating characteristics, courses of treatment, and outcomes in Korean patients with depressive disorders. Using the data from this study, the analyses presented here were carried out to investigate antidepressant prescribing patterns for the treatment of depressive disorders in real clinical settings over a 12-week treatment period.
The design and procedure of the study have also been described elsewhere.
All patients who visited the study hospitals seeking treatment for depression were candidate subjects for the study. Patients were assessed and diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
The CRESCEND study used broad inclusion criteria and minimal exclusion criteria to reflect real-world practices in Korea. Inclusion criteria were out- and inpatients aged over 7 years who were diagnosed with depressive disorders according to DSM-IV. Although there was no limitation to the baseline 17-item Hamilton Depression Rating Scale
The study was approved by all relevant university and hospital institutional review boards. All participants reviewed the consent form, and written informed consent was obtained by research staff before participation in the study. For participants aged less than 16 years, written consent was obtained from a parent or legal guardian, and written assent was obtained from the participant. For those who were very old or physically ill, the nature and purpose of the study were explained, and written informed consent was obtained from the person or his/her caregiver, as appropriate.
Socio-demographic characteristics were evaluated by a clinical research coordinator using the structured CRF. Data were obtained on age, gender, duration of formal education, marital status, cohabiting status, religious observation, current occupation, and monthly income. For this analysis, the following categories were applied: marital status (currently married or not), cohabiting status (living alone or not), religion (religious observance or not), occupation (currently employed or not), and monthly income (above or below 2,000 USD).
As mentioned above, depressive disorder diagnoses were made by the treating clinicians based on DSM-IV criteria. In a sub-sample of patients who gave consent, the DSM-IV based Structured Clinical Interview
Further assessment scales for evaluating symptoms and function were administered by the clinical research coordinators. The instruments administered were the HAMD, the Hamilton Anxiety Rating Scale
Drug treatment was performed in naturalistic patterns based on each clinician's decision; that is, all clinicians who participated in this study themselves decided on the prescriptions of antidepressants and concomitant medications, considering each patient's condition. All types, regimens, and doses of antidepressants were allowed by the study. Clinicians decided on treatment modalities according to patients' states at each visit.
For the purpose of the analyses, antidepressants were classified as follows: SSRIs (citalopram/escitalopram, paroxetine, fluoxetine, sertraline); newer dual-action antidepressants (mirtazapine, venlafaxine, bupropion); other antidepressants including TCAs (milnacipran, imipramine, amitriptyline, nortriptyline, dothiepine, trazodone). Treatment regimens were classified into monotherapy, switching, and combination. Monotherapy was defined as using only one antidepressant during the treatment period. Switching was defined as switching from one to another antidepressant, and combination was defined as the use of two or more antidepressants for most of the treatment period.
Any concomitant medications used to enhance efficacy and relieve associated symptoms of depression or to control adverse effects were allowed, according to the clinicians' decision. These were classified into antipsychotics, mood stabilizers, and anxiolytics/hypnotics. Antipsychotics included risperidone, olanzapine, quetiapine, aripirazole, amisulpride, ziprasidone, perphenazine, haloperidol, and pimozide. Mood stabilizers were lithium and valproic acid, an anticonvulsant. Anxiolytics/hypnotics were lorazepam, alprazolam, diazepam, clonazepam, clorazepate, ethyl loflazepate, zolpidem, flunitrazepam, and bromazepam. Other concomitant agents such as buspirone were also prescribed.
The results described here are restricted to data obtained in the initial 12 weeks of treatment in order to focus on the acute treatment of depressive disorders. We present the results in number and percentage (%) form for descriptive data using tables and figures.
We investigated the type of antidepressant(s) prescribed at the baseline visit and divided the treatment strategies used during the 12-week period of our investigation into monotherapy; switching, i.e., switching to another antidepressant; and combination, i.e., concomitant use of other agents besides antidepressants (augmentation) and concomitant use of antidepressants (combination). The use of anxiolytic/hypnotics during the study period was also investigated. In addition, information on the timing of switching, augmentation, and combination therapy was collected. These prescription patterns were compared again by the treatment setting, baseline HAMD and HAMA scores, and psychotic features using χ2 or Fisher's exact tests.
A total of 1,183 patients were enrolled in the CRESCEND study, and data from 723 (61%) patients were eligible for the present analysis; that is, these patients scored more than 14 on the HAMD and were taking antidepressants for up to 12 weeks, following the clinical decision of a clinician. Patients who had one or more visits after the baseline evaluation were included in the analysis. Patients disposition by hospitals and provinces was as follow: 181 at the Saint Mary's Hospital of the Catholic University, 243 at the Korea University Hospital, 28 at the Soonchunhyang University Hospital, 25 at the Hanyang University Hospital, and 2 at the Samsung Medical Center located in Seoul; 39 at the Kangwon National University Hospital in Kangwon province; 89 at the Kyemyung University Hospital and 1 at the Kyungpook National University Hospital in Daegu; 1 at the Inje University Paik hospital and 1 at the Marynoll Hospital in Busan; 60 at the Chonnam National University Hospital and 12 at the Chosun University Hospital in Gwangju; and 41 at the Hwasun Chonnam National University Hospital in Jeollanam province.
Baseline socio-demographic and clinical characteristics of the patients are shown in
With respect to prescribing patterns by the treatment setting, the initial antidepressants prescribed for inpatients were 48.3% SSRIs, 45.7% newer dual-action antidepressants, and 6.0% other antidepressants; and for outpatients were 49.3% SSRIs, 45.8% newer dual-action antidepressants, 4.9% other antidepressants. There were no significant differences in the choice of initial antidepressant between the inpatients (n=151) and outpatients (n=572) (p=0.866). In addition, the HAMD and HAMA scores did not affect the choice of initial antidepressant [HAMD score ≥22 (n=324) vs. <22 (n=399), p=0.179; and HAMA score ≥20 (n=339) vs. <20 (n=384), p=0.63].
According to the data, regardless of the initial antidepressant prescribed, the largest proportion of patients received antidepressant monotherapy for most of the study period. Overall, 67.6% to 71.3% of patients were maintained on antidepressant monotherapy according to the initial antidepressants. Combination treatment with more than one antidepressant was used for 24.3% to 26.0% of patients. Switching from the initial antidepressant to another antidepressant occurred in 3.7% to 8.1% of patients.
When an SSRI was initially prescribed, 38.5% of patients were switched to other SSRIs, and 46.2% and 15.3% were switched to newer dual-action antidepressants and other antidepressants, respectively. When a newer dual-action or other antidepressant was the initial antidepressant, 70.6% of patients taking newer dual-action antidepressants and 66.7% of those taking other antidepressants, respectively, were switched to SSRIs; 23.5% of prescriptions for newer dual-action drugs were changed to another dual-action drug, and 33.3% of prescriptions for other medications were switched to a newer dual-action antidepressant. The proportion of patients switching from newer dual-action antidepressants to other antidepressants including TCAs was only 5.9% (
When SSRIs were initially prescribed, 67.4% of initial SSRIs were combined with newer dual-action antidepressants, and 22.5% and 10.1% were combined with other antidepressants including TCAs and other SSRIs, respectively. When newer dual-action antidepressants were the initial antidepressant, other antidepressants including TCAs were most commonly added for combination treatment (50%), followed by other newer dual-action antidepressants (28.1%) and SSRIs (20.9%). When other antidepressants including TCAs were initially prescribed, newer dual-action antidepressants were most commonly added (44.5%), followed by SSRIs (33.3%) and other antidepressants including TCAs (22.2%) (
Of all prescriptions for antidepressants, 20.6% were augmented by other agents, and of these, 75.1% were used concomitantly with anxiolytics or hypnotics. The rates of concomitant medication according to the class of antidepressant are shown in
Most physicians (91%) tended to use anxiolytics or hypnotics concomitantly from the beginning of antidepressant treatment. A considerable portion (56.4%) of the concomitant use of other agents besides antidepressants started within 1 week of beginning treatment. However, 42.4% of antidepressant switching occurred after 2 weeks of treatment, and 36.4% and 21.2% of switching occurred after 3 and 4 weeks of treatment, respectively. With respect to initiation of combination treatment, 38% of such combinations were started during the first week of treatment, and 27.7% and 14.7% were started during weeks 2 and 3, respectively. Only 19.6% of combination treatments were started during week 8.
Data on the prescription of antidepressants in real-world psychiatric practice in Korea is limited. Most previous studies have used survey research or investigated the prescribing pattern in just one hospital. The CRESCEND study was planned to reflect the actual psychiatric clinical picture throughout Korea and its strength is that it is representative of Korea in terms of both sample size and the source of patients. To our knowledge, this study was the first nationwide prospective clinical study on Korean patients with depressive disorders. The results of this study show that many changes have occurred in Korean psychiatrists' prescribing of antidepressants.
A previous study in Korea, reported in 2003, found that SSRIs were preferred by many psychiatrists (70%) as first-line agents for the treatment of major depressive disorder (MDD), and a much lower proportion of respondents (8%) preferred newer dual-action antidepressants, including mirtazapine and venlafaxine.
The present study showed that the use of venlafaxine has also increased. A recent meta-analysis suggested that venlafaxine was associated with greater response (odds ratio 1.15) and remission (odds ratio 1.19) in the treatment of MDD, compared with SSRIs.
Although venlafaxine is known to be associated with sympathomimetic cardiovascular effects including hypertension and prolonged heart rate-corrected QT interval,
With regard to switching, when the initial antidepressants were SSRIs, the most common switch was to newer dual-action antidepressants (46.2%) followed by switching to other SSRIs (38.5%). When the initial antidepressants were non-SSRIs, switching to SSRIs was most common (about 70%). In terms of individual agents, switching to venlafaxine, a newer dual-action antidepressant, was most common (21.2%), followed by SSRIs including escitalopram (18.2%). The Korean Medication Algorithm for Major Depressive Disorder (KMAP-MD) suggests that switching from the initial antidepressant to venlafaxine and other SSRIs is reasonable in patients who failed to respond to the initial antidepressant.
One notable finding of the present study concerns the timing of switching. Most current treatment guidelines for MDD recommend the continuous use of antidepressants for 4 to 8 weeks.
Among the patients in this study, 25% received antidepressant combination treatment. The concomitant use of two antidepressants is controversial because of possible adverse effects and questionable clinical benefits.
In terms of the classes of antidepressants that may be combined, the present study found that when initial antidepressants were SSRIs, newer dual-action antidepressants were most frequently prescribed as concomitant antidepressants (67.4%). A previous study to investigate the general practice of psychiatrists reported that SSRI plus mirtazapine was the most popular first-choice combination.
Interestingly, however, amitriptyline was the most commonly used concomitant antidepressant (29.9%). Jung et al.
Augmentation treatment with non-antidepressant agents can be used to accelerate treatment response. We found that about 20% of patients received augmentation treatment and the most commonly used augmenting agent was an antipsychotic. Atypical antipsychotic agents (52.3%) were more frequently prescribed than were typical antipsychotics (4.1%). Growing evidence suggests that other atypical antipsychotics are also associated with antidepressant effects through 5-HT2 receptor antagonism and 5-HT1A and dopamine receptor partial agonistic activity.
This study showed that buspirone accounted for 28.2% of all concomitant use of agents in the "other antidepressant" category. Buspirone was first proposed for use in an augmentation strategy in the 1990s, but a controlled study found that the concomitant use of buspirone was no more effective than the addition of a placebo.
In another paper from the same dataset of our study group, we investigated the relationship between a history of a suicide attempt and treatment characteristics. In brief, we did not find significant difference between patients with and without a history of a suicide attempt in the choice of antidepressant or the use of concomitant medications including antipsychotic agent. However, mood stabilizers were more frequently prescribed in patients with a history of a suicide attempt.
In terms of anxiolytics and hypnotics including benzodiazepine, we found that about 75% of patients received benzodiazepine. A combination of antidepressant and benzodiazepine appears to be common practice throughout the world. However, the advantages of this combination treatment are unclear. Fava et al.
This study has some limitations. Firstly, this is an open-label naturalistic study for the treatment of depressive patients. The naturalistic design was both a strength and potential limitation. The broad inclusion and minimal exclusion criteria for recruitment, and the absence of limitations placed on treatment were designed to reflect real clinical situations as closely as possible and maximize generalizability to clinical practice. However, because the treatment modality was determined by the choice of the treating clinician rather than by any formal guideline, inter-clinician variability might affect observed outcomes. Secondly, most patients were recruited from the university hospitals (16 of 18 hospitals), which can affect the prescription patterns. Lastly, approximately three-fourths of patients were enrolled from outpatient settings. There are possibilities that patients who were enrolled were less severe and treatment setting affected the prescription patterns. However, we found that there were no significant differences in the prescription patterns according to the treatment setting (inpatient or outpatient).
Overall, the CRESCEND study, a nationwide naturalistic study, has several important implications for clinicians. Firstly, there is a gap between current treatment guidelines and real-world practice. The results of this study show the real trends of prescription practice in Korea, namely, that the choice of antidepressants and the concomitant use of other agents have become increasingly diversified as newer agents, such as dual-action antidepressants and atypical antipsychotics, have been introduced into Korea. The concomitant use of antidepressants and atypical antipsychotics including quetiapine has been increasing. In addition, the concomitant use of other agents seems to start from the early phase of treatment, and an early switching strategy is commonly used. Further systematic studies are required to develop new treatment guidelines for depression that are suited to Korean society today, that reflect changes in prescribing patterns in real practice, and that consider new research evidence in the treatment of depression. In addition, further studies to compare the results of this study with those of the National Health Insurance database will be useful to examine the actual Korean antidepressants prescription pattern.
This research was supported by a grant of the Korea Health 21 R&D, Ministry of Health and Welfare, Republic of Korea (A050047, PI: TY Jun).
The prescribing pattern of antidepressants as first-line treatment.
The switching pattern from the initial antidepressant to another one.
The pattern of combination antidepressant treatment according to the initial antidepressant.
The concomitant use of non-antidepressant agents including anxiolytics/hypnotics according to the initial antidepressant. Augmentation agents include antipsychotics, lithium, and anticonvulsants.
Demographic and clinical characteristics of the study population
N: number, SD: standard deviation, USD: United States dollar, IQR: interquartile range