od and the date of the incident SSRI prescription was termed the index date. The enrolment period was selected based on the addition of depression to the UK Quality and Outcomes Framework (QOF) (http://www.qof.ic.nhs.uk) in 2006 and to ensure an adequate follow-up period to assess outcomes. Patients were followed-up up to a maximum date of 25th October 2010 where data was available. To identify patients with a diagnosis in their clinical record in the period from 6 months before to 3 months after the index date, a specific Read code list for MDD was compiled from synonyms, relevant code stems, and the UK Quality and Outcomes Framework (QOF) depression rule set for MDD (http://www.qof.ic.nhs.uk/).
Because GPs do not always enter a specific Read code for a diagnosis for MDD [9,10], records with depression questionnaire scores were also captured to identify patients who scored above the cut-off for MDD in the period from the index date to six months prior to the index date. The recommended questionnaires by the QOF are the Patient Health Questionnaire (PHQ) , Hospital Anxiety and Depression Scale (HADS)  and the Beck Depression Inventory II (BDI-II) , which each have high sensitivity and specificity for detecting MDD. The patient’s record was also required to have at least one day of follow up data after the index date.
Patient records were excluded if they: 1) had a prescription for an SSRI or any other antidepressants in their record prior to the index date; 2) had less than 12 months of computerized data prior to the index date; 3) were not considered as “acceptable” according to GPRD’s data quality criteria; and 4) had an index date prior to the practice becoming a GPRD Up-to-Standard practice (i.e. the date that the practice was deemed to have continuous high quality data fit for use in research).
2.3. Defining Treatment Outcomes
Drug code lists were compiled for antidepressants and other psychotropic medications, including antipsychotics, anxiolytics, antimanics and stimulants, by using the British National Formulary (BNF) as a guide (http://bnf.org/bnf/), and these lists were used to identify the relevant prescriptions. For each patient, the treatment trajectory was tracked for each separate line of treatment, up to four lines. The first (index) line was comprised of the initial SSRI treatment. A new treatment line was defined by a change from the preceding treatment line into one of the treatment regimens defined in Box 1.
The prospective trajectory of each patient’s therapy profile since index date was characterized to indicate the therapy outcome for each line of treatment.
2.4. Healthcare Resource Utilization
MDD-related GP visits were identified using relevant Read code entries for depression, prescriptions for antidepressants, and referrals to specialists, such as psychiatrists and psychologists.
Covariates included patient age, gender, and comorbid conditions, including other psychopathologies (anxiety,
Box 1. Treatment outcomes for defining lines of treatment.
and alcohol/substance misuse) and chronic pain conditions (e.g. trigeminal neuralgia, osteoarthritis, irritable bowel syndrome and migraine, etc.). Additionally, the Charlson Comorbidity Index (CCI) [14,15] was calculated for each patient. The CCI measures 17 medical conditions, such as AIDS, cardiovascular disease, cancer, diabetes, liver and renal disease, and, rheumatologic disease. Weights are assigned according to risk of death from the condition [14,15].
2.6. Statistical Analysis
Incidence of treatment outcomes was calculated using survival analysis methods, and longitudinal trends were examined from the index date through all available data. The incidence rates were calculated using person years at risk, which is defined as the cumulative time contributed in years by the at risk population, and allows for the differing lengths of follow-up among patients. The first event of each treatment outcome was identified, and hazard rates were calculated using Kaplan-Meier methods to examine trends over time. A multivariable analysis of incidence of adjunctive therapy was carried out using Poisson regression, adjusting for patient demographics, index SSRI, depression severity, psychopathologies, chronic pain comorbidities, overall comorbidity burden, and year of enrolment into the study. Wald tests were used for modelling. Annual incidence of MDD-related patient visits to the GP were calculated by line of therapy; the exposure period started from commencement of the line of therapy up to the earlier of either the end of the therapy line or six months after the line start date. The 95% confidence intervals were adjusted to account for the clustered data (i.e. multiple GP visits per patient).
The study was reviewed and approved by the GPRD Independent Scientific Advisory Committee (ISAC).
All data were analysed using Stata 11.2 (StataCorp LP, College Station, Texas).
94,932 patients were identified as receiving an incident prescription for an SSRI. Of these patients, 2059 had a recent Read code entry for MDD, and an additional 13,215 scored positively for MDD on a depression screening questionnaire, resulting in a final study cohort of 15,274 patients.
3.1. Patient Characteristics
Median age of patients was 38.0 years (10th to 90th percentiles, 21.0 - 63.0); 9100/15,274 (59.6%) were female; and 13,297/15,274 (91.2%) patients had at least a year of follow-up data after the index date. The initial SSRI prescription was most likely citalopram (N = 7468, 48.9%), followed next by fluoxetine (N = 6477, 42.4%). Relatively fewer numbers of patients received sertraline (N = 612, 4.0%), escitalopram (N = 555, 3.6%), paroxetine (N = 161, 1.1%) or fluvoxamine maleate (N = 1, 0.01%) as their first-line therapy.
3.2. Patterns of Adjunctive Therapy and Other Treatment Outcomes
Table 1 shows the annual incidence of treatment outcomes since index SSRI treatment (first-line therapy), both overall and by lines of therapy (2nd line, 3rd line, 4th line). The overall incidence of adjunctive therapy was 3.07/100 person years (95% CI 2.90 - 3.25), with the incidence being highest in line two of treatment. The annual incidence of adjunctive therapy was lower than that of all other treatment patterns examined except for combination therapy. The incidence of a dose increase for the index SSRI was 6.23/100 person years (95% CI 5.98 - 6.50). Overall incidence of switches in therapy was 8.57/100 person years (95% CI 8.28 - 8.88), and again was highest in the second-line. Restart of therapy after discontinuation was relatively high with an overall incidence of 15.00/100 person years (95% CI 14.61 - 15.40), and was highest in line two of therapy (Table 1).
Figure 1 shows Kaplan-Meier curves for the first event of each treatment outcome after the index date. At 12 months after index, 5% of patients had received adjunctive therapy, and this rate increased slowly over time to 7% of patients at 24 months, 9% at 36 months and 11% at 48 months after index. Combination therapy followed a similar pattern compared with adjunctive therapy. Switch in therapy was a slightly different treatment pattern
Table 1. Annual incidence of treatment outcomes since index, by lines of therapy (a2nd - 4th).
with a higher proportion of patients receiving a switch earlier than other treatment options: 10% at four months, 14% at 12 months, 17% at 24 months, and 21% at 48 months after index. Patients who received a dose increase for their index SSRI did so relatively early on with 11% with a first dose increase at 3 months after index; this rate did not rise substantially over time with 14% of patients having a dose increase by 48 months. Restarts in antidepressant therapy, in comparison, increased considerably over time, with 45% of patients having restarted therapy at 48 months after index.
3.3. Multivariable Analysis for Predictors of Adjunctive Therapy
Table 2 shows the multivariable analysis for the first incidence of adjunctive therapy after index. Patients who enrolled in the study in 2008 were 29% more likely to have had adjunctive therapy compared with those who enrolled in 2006 (p = 0.002). Females were 16% more likely to have had adjunctive therapy compared with males (p = 0.03). Greater age was strongly associated with adjunctive therapy, with the largest association in the elderly (60+ years) who were approximately twice as likely to have received adjunctive therapy compared with those aged 18 - 29 years (p < 0.001). Increasing depression severity score (p = 0.003) and CCI score (p = 0.01) were each associated with a higher likelihood of adjunctive therapy. Finally, patients with irritable bowel syndrome (IBS) were 46% more likely to have had adjunctive therapy (p = 0.001).
3.4. Healthcare Resource Utilization
Table 3 shows the incidence of MDD-related patient visits to the GP by therapy outcomes and line of treatment.
Figure 1. Kaplan-Meier failure curves (hazards) for first event of therapy outcomes after index.
Table 2. Multivariable analysis of first incidence of adjunctive therapy (N = 12,573).
Table 3. Annual incidence of MDD relateda patient visits to GP, by treatment line and by therapy outcomes within linesb.
Across lines of treatment, the incidence of GP visits was consistently lower for adjunctive therapy compared to SSRI dose increase, antidepressant switching, and combination treatment. The incidence of GP visits was lowest for restarts in antidepressant therapy.
This study assessed the incidence and predictors of adjunctive therapy among patients with MDD in UK primary care in the context of overall treatment patterns and healthcare resource utilisation. Adjunctive therapy was examined by line of therapy along with other outcomes on the treatment trajectory including dose increases, drug switches, combination therapy and restart of antidepressant therapy. As such, it provides a comprehensive description of the current management of MDD patients who are inadequate responders to initial treatment with antidepressants in UK primary care.
The overall incidence for adjunctive therapy (3.07/100 person years) and for combination therapy was low compared with the incidence of either a dose increase or a drug switch. A study of 12 European countries, including the UK, found the prevalence of adjunctive antidepressant therapy to be less than 7% . Similarly, a study in Spain found the prevalence of adjunctive antidepressant therapy to be 8.3% among patients treated for MDD ; several other studies have reported a range of adjunctive therapy prevalence of between 2% to 25% [16,18,19]. Reflecting a different health care system, a study based on a US insurance claims database found that 38% of patients who initiated on SSRI monotherapy received adjunctive treatment in the year following the initial index prescription .
The relatively low rates of adjunctive therapy observed in the present UK primary care study may be explained by the stepped-care model of treatment recommended by NICE  which advocates the initiation and management of depression in primary care, but recommends more complex interventions, including those for treatment-resistant depression, to be initiated only by mental health specialists . This model of recommended treatment steps may also explain the surprising finding of adjunctive therapy most commonly occurring as early as the second-line of treatment. Possibly, the adjunctive therapy patients that were observed within primary care may have been those who were relatively stable with respect to their treatment response and had been transferred from specialist to primary care for maintenance treatment. Hence, it is possible that the database does not reflect the full trajectory of treatment for MDD in primary care. In addition, MDD-related GP consultation rates among those receiving adjunctive therapy in a given line were less frequent than for patients who received other treatment options. This finding may reflect that patients who get adjunctive therapy receive shared care from both a mental health specialist and a GP, therefore these particular patients would be likely to consult their GPs less for their depression than MDD patients on monotherapy who are solely seeking treatment from a GP.
Several factors were associated with the first incidence of adjunctive therapy. First, patients initiating therapy for MDD in 2008 were more likely to receive adjunctive therapy compared with those initiating therapy in 2006. This finding suggests that treatment patterns in the UK are in flux and may indicate an increasing proclivity towards adjunctive therapy prescribing in primary care in recent years. This trend may likely be reinforced with the recent approval in 2010 of the atypical antipsychotic Seroquel XL® (quetiapine prolonged release) as an adjunctive agent for MDD patients who have had sub-optimal response to antidepressant monotherapy (http://www.ema.europa.eu).
With regard to predictors of adjunctive therapy, females were more likely to receive adjunctive therapy compared with males, possibly relating to the greater incidence, duration, and chronicity of depression that occurs in women compared with men [21,22]. Females, compared with males, may have a more complex treatment trajectory that requires multifaceted interventions such as adjunctive therapy. Greater health-seeking behaviours in females for overall medical care, compared with males, may also be a contributory factor as men may have less opportunity to fully explore the treatment options when experiencing an inadequate response to antidepressant therapy [22-24]. Age was also predictive of adjunctive therapy, with the highest magnitude among those aged 60 years and older. Depression in the elderly can have a poorer prognosis with high rates of relapse and chronicity [25,26] as well as a slower response to antidepressants compared with younger patients . Moreover, the elderly are at higher risk of adverse outcomes from their depression, such as suicide. Hence, adjunctive therapy among elderly patients may be necessary to ensure that they are adequately treated. Also, the elderly tend to have more somatic disorders than younger people and higher associated GP consultation rates , thus, providing more opportunity to seek treatment for MDD.
Illness severity was also predictive of adjunctive therapy. Not only was severity of depression associated with likelihood of adjunctive treatment, but a higher burden of general comorbidity and the presence of IBS were associated with higher incidence of adjunctive therapy compared with patients without these comorbidities. Similarly as observed with the elderly, more frequent consultations with GPs due to comorbidity may increase opportunity for the use of adjunctive treatment for MDD; furthermore, patients with comorbid conditions often fare worse in terms of both their depression and their comorbid condition [26,28,29].
Strengths and Limitations
The GPRD provided longitudinal data on a large sample of MDD patients and good statistical power for examining the trajectory of treatment for MDD in UK primary care. Patients on SSRIs who had a definitive diagnosis for MDD were specifically selected, since SSRIs can also be used to treat other conditions such as anxiety.
Several limitations should be noted:
1) GPs may not enter diagnoses according to DSM IV or ICD criteria, and MDD patients without a specific Read code for MDD (i.e., only a general code for depression) and no depression screening questionnaire score may have been missed in the database.
2) The GPRD contains information on drugs prescribed and does not verify whether the medication was dispensed or taken by the patient.
3) Data included only the comorbidities for which the patient had consulted and that the GP had recorded.
4) The predictors of adjunctive therapy may not be generalizable to the population of MDD patients outside of primary care.
5. CONCLUSION AND IMPLICATIONS
While this study demonstrated that certain groups such as females, older people, those with a higher comorbidity burden, and those initiating treatment in recent years were more likely to receive adjunctive therapy, the overall rates of adjunctive therapy in primary care were low relative to other treatment strategies such as SSRI dose increases and antidepressant switching. According to UK treatment guidelines, adjunctive therapy is likely to be initiated by mental health specialists. However this study shows little evidence of shared care maintenance treatment by GPs. Patients with partial and non-response may also not be referred for specialist care and hence may remain undertreated for their MDD. Given the high rates of inadequate response to antidepressant monotherapy, patients who initiate adjunctive therapy in specialist care may benefit from maintenance treatment from their GP under a shared-care arrangement .
Thanks are due to Dr. Andrew Copas for providing statistical advice.