Withdrawal of unnecessary antidepressant medication: a randomised controlled trial in primary care

Background Antidepressant use has increased exponentially in recent decades, mostly due to long continuation. Aim To assess the effectiveness of a tailored recommendation to withdraw antidepressant treatment. Design & setting Randomised controlled trial in primary care (PANDA study) in the Netherlands. Method Long-term antidepressant users (≥9 months) were selected from GPs prescription databases. Patients were diagnosed with the Composite International Diagnostic Interview (CIDI). Long-term users without indication for maintenance treatment (overtreatment) were selected. The intervention consisted of disclosure of the current psychiatric diagnosis combined with a tailored treatment recommendation. Patients were followed for 12 months. Results The study included 146 participants from 45 family practices. Of the 70 patients in the intervention group, 34 (49%) did not comply with the advice to stop their antidepressant medication. Of the 36 (51%) patients who agreed to try, only 4 (6%) succeeded. These figures were consistent with the control group, where 6 (8%) of the 76 patients discontinued antidepressant use successfully. Patients who were recommended to discontinue their antidepressant medication reported a higher relapse rate than the control group (26% versus 13%, P = 0.05). Conclusion Changing inappropriate long-term antidepressant use is difficult.


Introduction
The incidence of complete Achilles tendon rupture is 18 per 100 000 patient-years 1 and is usually diagnosed clinically by GPs.The extent of clinical misdiagnosis is unknown in Norway, but may be high. 2This is important as delayed treatment has unfavourable consequences. 1,3We report how a GP, with no clinical ultrasound experience, recorded images with a pocket-sized ultrasound device (PSUD) under supervision to confirm a complete Achilles tendon rupture.This could present a new indication for GP ultrasound.

Case report
A 36-year-old man experienced acute pain above the right heel accompanied by an audible snap while sprinting.He immediately had difficulty walking and 3 hours later consulted an on-call GP.Posterior ankle swelling with a tender depression 3 cm proximal to the calcaneum was found.Active plantar flexion against resistance was weak and Simmonds-Thompson test was 'partially positive' on applying a strong calf-squeeze.Based on these findings, calf muscle rupture was diagnosed as the Achilles tendon was thought to be intact.The patient was advised to elevate the foot and wait 2 weeks for improvement.Two days later a second GP, who was aware of a history of an audible snap, considered complete tendon rupture and reexamined the patient.Findings included an absent right heel raise due to weakness, minimal active plantar flexion against gravity and lying prone, significant right ankle swelling without bruising, and an altered angle of declination.Palpation elicited no ankle bony tenderness, yet a painful gap was identified 6 cm proximal from the calcaneal attachment, along the line of the Achilles tendon.Simmonds-Thompson's test was clearly positive.The positive Simmond's triad indicated a clinical diagnosis of complete rupture of the Achilles tendon.
A 3.4-8 MHz linear array probe PSUD (VScanÔ dual probe, GE Healthcare), set at a depth of 3.5 cm, was used under the supervision of a rheumatologist experienced in ultrasound.The tendon was enlarged from 1 cm to 6 cm above the calcaneal insertion, where a clear gap was seen (Figure 1).Two hours later a radiologist-performed ultrasound (LOGIQ E9Ô, GE Healthcare) and reported an enlarged distal tendon and a complete rupture at 5-6 cm from the calcaneal attachment, creating a 2.7 cm blood-filled gap (Figure 2).Surgical exploration 8 days post-injury found a complete Achilles tendon rupture '5-10 cm above the ankle joint'.

Discussion
Tromsø Hospital serves a large area with a population of approximately 160 000.Between 2010-2014 an average of 21 patients per year were referred by their GP for suspected Achilles rupture.

Introduction
The incidence of complete Achilles tendon rupture is 18 per 100 000 patient-years 1 and is usually diagnosed clinically by GPs.The extent of clinical misdiagnosis is unknown in Norway, but may be high. 2This is important as delayed treatment has unfavourable consequences. 1,3We report how a GP, with no clinical ultrasound experience, recorded images with a pocket-sized ultrasound device (PSUD) under supervision to confirm a complete Achilles tendon rupture.This could present a new indication for GP ultrasound.

Case report
A 36-year-old man experienced acute pain above the right heel accompanied by an audible snap while sprinting.He immediately had difficulty walking and 3 hours later consulted an on-call GP.Posterior ankle swelling with a tender depression 3 cm proximal to the calcaneum was found.Active plantar flexion against resistance was weak and Simmonds-Thompson test was 'partially positive' on applying a strong calf-squeeze.Based on these findings, calf muscle rupture was diagnosed as the Achilles tendon was thought to be intact.The patient was advised to elevate the foot and wait 2 weeks for improvement.Two days later a second GP, who was aware of a history of an audible snap, considered complete tendon rupture and reexamined the patient.Findings included an absent right heel raise due to weakness, minimal active plantar flexion against gravity and lying prone, significant right ankle swelling without bruising, and an altered angle of declination.Palpation elicited no ankle bony tenderness, yet a painful gap was identified 6 cm proximal from the calcaneal attachment, along the line of the Achilles tendon.Simmonds-Thompson's test was clearly positive.The positive Simmond's triad indicated a clinical diagnosis of complete rupture of the Achilles tendon.
A 3.4-8 MHz linear array probe PSUD (VScanÔ dual probe, GE Healthcare), set at a depth of 3.5 cm, was used under the supervision of a rheumatologist experienced in ultrasound.The tendon was enlarged from 1 cm to 6 cm above the calcaneal insertion, where a clear gap was seen (Figure 1).Two hours later a radiologist-performed ultrasound (LOGIQ E9Ô, GE Healthcare) and reported an enlarged distal tendon and a complete rupture at 5-6 cm from the calcaneal attachment, creating a 2.7 cm blood-filled gap (Figure 2).Surgical exploration 8 days post-injury found a complete Achilles tendon rupture '5-10 cm above the ankle joint'.

Introduction
The incidence of complete Achilles tendon rupture is 18 per 100 000 patient-years 1 and is usually diagnosed clinically by GPs.The extent of clinical misdiagnosis is unknown in Norway, but may be high. 2This is important as delayed treatment has unfavourable consequences. 1,3We report how a GP, with no clinical ultrasound experience, recorded images with a pocket-sized ultrasound device (PSUD) under supervision to confirm a complete Achilles tendon rupture.This could present a new indication for GP ultrasound.

Case report
A 36-year-old man experienced acute pain above the right heel accompanied by an audible snap while sprinting.He immediately had difficulty walking and 3 hours later consulted an on-call GP.Posterior ankle swelling with a tender depression 3 cm proximal to the calcaneum was found.Active plantar flexion against resistance was weak and Simmonds-Thompson test was 'partially positive' on applying a strong calf-squeeze.Based on these findings, calf muscle rupture was diagnosed as the Achilles tendon was thought to be intact.The patient was advised to elevate the foot and wait 2 weeks for improvement.Two days later a second GP, who was aware of a history of an audible snap, considered complete tendon rupture and reexamined the patient.Findings included an absent right heel raise due to weakness, minimal active plantar flexion against gravity and lying prone, significant right ankle swelling without bruising, and an altered angle of declination.Palpation elicited no ankle bony tenderness, yet a painful gap was identified 6 cm proximal from the calcaneal attachment, along the line of the Achilles tendon.Simmonds-Thompson's test was clearly positive.The positive Simmond's triad indicated a clinical diagnosis of complete rupture of the Achilles tendon.
A 3.4-8 MHz linear array probe PSUD (VScanÔ dual probe, GE Healthcare), set at a depth of 3.5 cm, was used under the supervision of a rheumatologist experienced in ultrasound.The tendon was enlarged from 1 cm to 6 cm above the calcaneal insertion, where a clear gap was seen (Figure 1).Two hours later a radiologist-performed ultrasound (LOGIQ E9Ô, GE Healthcare) and reported an enlarged distal tendon and a complete rupture at 5-6 cm from the calcaneal attachment, creating a 2.7 cm blood-filled gap (Figure 2).Surgical exploration 8 days post-injury found a complete Achilles tendon rupture '5-10 cm above the ankle joint'.

Discussion
Tromsø Hospital serves a large area with a population of approximately 160 000.Between 2010-2014 an average of 21 patients per year were referred by their GP for suspected Achilles rupture.

Introduction
The incidence of complete Achilles tendon rupture is 18 per 100 000 patient-years 1 and is usually diagnosed clinically by GPs.The extent of clinical misdiagnosis is unknown in Norway, but may be high. 2This is important as delayed treatment has unfavourable consequences. 1,3We report how a GP, with no clinical ultrasound experience, recorded images with a pocket-sized ultrasound device (PSUD) under supervision to confirm a complete Achilles tendon rupture.This could present a new indication for GP ultrasound.

Case report
A 36-year-old man experienced acute pain above the right heel accompanied by an audible snap while sprinting.He immediately had difficulty walking and 3 hours later consulted an on-call GP.Posterior ankle swelling with a tender depression 3 cm proximal to the calcaneum was found.Active plantar flexion against resistance was weak and Simmonds-Thompson test was 'partially positive' on applying a strong calf-squeeze.Based on these findings, calf muscle rupture was diagnosed as the Achilles tendon was thought to be intact.The patient was advised to elevate the foot and wait 2 weeks for improvement.Two days later a second GP, who was aware of a history of an audible snap, considered complete tendon rupture and reexamined the patient.Findings included an absent right heel raise due to weakness, minimal active plantar flexion against gravity and lying prone, significant right ankle swelling without bruising, and an altered angle of declination.Palpation elicited no ankle bony tenderness, yet a painful gap was identified 6 cm proximal from the calcaneal attachment, along the line of the Achilles tendon.Simmonds-Thompson's test was clearly positive.The positive Simmond's triad indicated a clinical diagnosis of complete rupture of the Achilles tendon.
A 3.4-8 MHz linear array probe PSUD (VScanÔ dual probe, GE Healthcare), set at a depth of 3.5 cm, was used under the supervision of a rheumatologist experienced in ultrasound.The tendon was enlarged from 1 cm to 6 cm above the calcaneal insertion, where a clear gap was seen (Figure 1).Two hours later a radiologist-performed ultrasound (LOGIQ E9Ô, GE Healthcare) and reported an enlarged distal tendon and a complete rupture at 5-6 cm from the calcaneal attachment, creating a 2.7 cm blood-filled gap (Figure 2).Surgical exploration 8 days post-injury found a complete Achilles tendon rupture '5-10 cm above the ankle joint'.

Discussion
Tromsø Hospital serves a large area with a population of approximately 160 000.Between 2010-2014 an average of 21 patients per year were referred by their GP for suspected Achilles rupture.

Introduction
Last summer our small medical team visited the Calais 'Jungle'.Since that time much has changed and the camp is being demolished and by the time this article is read, it will probably be long gone.Some youngsters are finally being brought to the UK under the 'Dubs' amendment.However, once this camp is cleared it will not solve the ongoing flight of refugees from war torn areas: other camps are already appearing.

July 2016
A young Afghan man caught his finger on a sharp point while trying to cross a barbed wire fence.The finger was partially degloved.He attended the local hospital, where they placed a few sutures, but now, 2 weeks later, the skin is necrotic and the underlying tissue looks infected.He is in danger of losing his finger.
A middle-aged Sudanese man has been having rigors and is generally unwell.He says it is similar to when he last had malaria.
A young Ukrainian woman complains of lower back pain and urinary frequency.The paths of these three people may never have crossed; yet here they are, denizens of the Calais Jungle.They turn up to a makeshift primary care 'clinic' that we set up in the heart of the unofficial refugee camp one weekend in July 2016.
With only basic medical supplies, we are immediately challenged by what we see.How can we arrange secondary care for the young Afghan in danger of losing his finger?We try to persuade him to return to the original local hospital, but he is reluctant.It was not a good experience for him the first time round.
With the other two patients, it is easier.They can attend the Salam clinic run by a local association during weekdays.Later, we receive word that malaria has been confirmed in our Sudanese patient.
More people arrive, presenting with scabies, rat bites, tinea, chest infections, and wheezing from inhaling smoke from fires lit to cook and keep warm in their tents at night.We examine a severely malnourished 2-year-old boy.We meet several of the camp's 600 unaccompanied children, at grave risk of sexual exploitation.We learn that there is inadequate safeguarding in place to protect them.A young Eritrean man comes in worried about his eye.He has sustained direct ocular trauma from a rubber bullet, and will never see normally again out of that eye.We see haematomas from police batons, and hear about children being exposed to tear gas again and again (Figure 1).

The reality
These are no ordinary patients.They have travelled far from home to escape war, poverty, and misery.They have endured personal odysseys to get here, experienced untold hardships, and suffered unimaginable privations.Many have survived the loss of their families, torture, and rape.Their journeys over, for the moment at least, they must make their homes in the Calais Jungle.Their new shelters are in many cases mere tarpaulin covers, and their new beds just rugs on the ground.They own next to nothing.There is little for them to do, besides use their ingenuity to cross the English Channel in search of a better life.They are vulnerable to exploitation, crime, injury, and disease.Potentially violent clashes with local police, with other ethnic groups resident in the Jungle, or local far

Introduction
2][3] Efforts were made to increase quality of care, and prescription rates for antidepressants increased. 4ow, contrary concerns are raised concerning overtreatment with antidepressants. 5][8][9][10] Studies suggest that many longterm users are exposed to antidepressants unnecessarily. 8,11,12One-third of long-term antidepressant users have been found to have no identifiable justification. 12In addition, a lack of medication review during the continuation of antidepressant treatment has been highlighted. 8][15][16] Overtreatment with antidepressants is problematic.The effectiveness is questionable: about five of every six antidepressant users do not benefit. 17From the GP perspective, it is important to discuss how patients can use their own resources to cope with their problems; providing medication might be counterproductive, as medication use may disincentivise a patient to find non-pharmacological solutions, thereby diminishing patient empowerment in a context where regaining control is essential for recovery. 18his study concludes that overtreatment with antidepressants is very prevalent and that a considerable proportion of long-term use has no clinical justification.As such, this study aims to reduce inappropriate long-term antidepressant use in general practice.The authors will evaluate the effectiveness of a recommendation to cease antidepressant treatment which is tailored to both the patient and the psychiatric diagnosis.

Method Study design
The authors conducted a cluster randomised controlled trial in primary care. 19The original protocol consisted of an overtreatment and an undertreatment trial.This article reports on the overtreatment trial.A summary can be found at the Nederlands Trial Register (NTR2032) (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2032).

Selection of study subjects
The study was conducted in 45 general practices in the Netherlands between February 2010 and March 2013.GPs identified long-term antidepressant users in their prescription database.GPs excluded patients based on the exclusion criteria below.follow-up CIDI, as well as in self-report questionnaires.Missing and contradicting prescriptions were checked by contacting the GP.

Secondary outcome
The severity of general distress and depressive symptoms was assessed by the Brief Symptom Inventory (BSI-53), 24 and the Centre for Epidemiological Studies Depression Scale (CESD), 25 at baseline and after 3, 6, 9 and 12 months' follow-up.Somatic comorbidity was assessed with the TiC-P questionnaire. 26

Sample size estimation
The prospective sample size estimation aimed to provide at least 85% power for two-tailed testing with a type-1 error rate of 5%.To account for the cluster-randomisation, an intraclass correlation of 0.05 was used.Assumptions with respect to recruitment and outcomes were difficult to estimate.A 20% discontinuation rate for the control and 50% for the intervention group was expected.Spontaneous non-adherence to antidepressants is found to be 25%, 27 and it was expected that this rate would decline as treatment time elapsed.9] An average Dutch general practice (2400 patients) has approximately 50-60 patients using antidepressants longterm, 30 with one-third possibly doing so inappropriately. 8This study's recruitment rate was based on the results of three GPs piloting patient recruitment in their practices.It was found that an average practice would be able to recruit three patients who fulfilled all of the inclusion criteria and none of the exclusion criteria.Assuming a dropout rate of 25%, the required sample size was calculated as 34 practices and 136 patients.

Statistical analyses
Analyses were conducted in IBM SPSS Statistics (version 20).Outcome analyses were performed on an intention-to-treat basis.Patients with an unknown primary outcome were conservatively classified as not having discontinued the antidepressant medication.The secondary outcome measures were analysed using a mixed models procedure for repeated measures, thus accounting for any missing values.

Results
Forty-five practices participated.In total, 6442 long-term antidepressant users were identified, of whom 2411 (37%) were deemed eligible by their GP.Of these patients, 358 (15%) consented to participate and 146 were included in this study (Figure 1).

Study population
Patient characteristics were well balanced at randomisation; any differences were not statistically significant (Table 1).Figure 2 shows the distribution of patients and their outcomes.
General distress or depressive symptoms at 3 months (approximately the time of consultation with GP to discuss the given recommendation) were not predictive for acceptance of the recommendation to discontinue (mean BSI 0.4, 95% CI = 0.2 to 0.5; mean CESD 17, 95% CI = 13 to 21 versus mean BSI 0.4, 95% CI = 0.2 to 0.6; mean CESD 15, 95% CI = 11 to 18).

Primary outcome
In the intervention group, four patients (6%, 95% CI = 2 to 14) successfully discontinued their antidepressant use, in comparison to six patients (8%, 95% CI = 4 to 16) in the control group.When

Secondary outcomes
The study found a marginally significant higher relapse rate in the intervention group (n = 18/70; 26%) compared to the control group (n = 10/76; 13%) = 0.05).Comparison of patients who continued their antidepressants identified a non-statistically significant higher relapse rate in the intervention versus control group (25% versus 11%, P = 0.07).This difference was not associated with antidepressant discontinuation.
Figure 1 continued a Post-randomisation patients did not meet inclusion criteria (human error during inclusion process).b Patients who did not complete follow-up interview.c Patients excluded with unknown primary outcome (due to dual primary outcome, excluded cases are less than patients lost to follow-up; that is, antidepressant use known via GP prescription database).d Intervention group restricted to patients with the intention to comply to recommendation and patients excluded with unknown primary outcome.

Research
Patients who successfully discontinued their antidepressant did not differ from the rest of the study population in sex, age, type of antidepressant used (selective serotonin reuptake inhibitors, tricyclic antidepressants or other) or psychiatric diagnosis.However, the mean duration of antidepressant use appeared to trend toward a shorter duration in patients who successfully discontinued their antidepressant (5.7 years; 95% CI = 1.6 to 9.7 years versus 9.6 years, 95% CI = 8.3 to 11.0 years, P = 0.077).

Discussion Summary
This study shows the difficulty of discontinuing inappropriate long-term antidepressant use.Irrespective of the condition patients were allocated to, only 10 of the 146 patients with inappropriate longterm use of antidepressants (that is, use not recommended by clinical guidelines), were able to successfully stop in the year of the study.Half of the patients in this study rejected the recommendation to discontinue.Even when intending to comply, more than half (56%) ultimately did not.Interestingly, the number of patients in the control group spontaneously discontinuing their antidepressant was similar to the number of patients discontinuing their antidepressant in accordance with the recommendation.
A higher relapse rate was found in the intervention group.Strikingly, this was not associated with antidepressant discontinuation (Figure 2).Focusing on the use of the antidepressant could have caused a higher risk of relapse; patients could have felt obliged to act on this recommendation Research without an internal motivation, causing more anxiety about potential relapse and, consequently, a higher risk of actual relapse.In addition, it is possible that feelings of failure could arise when rejecting the recommendation, again resulting in a higher risk of relapse.

Strengths and limitations
As far as the authors are aware, this is the first randomised controlled clinical trial focusing on longterm antidepressant use in patients in remission.
The studied intervention was based on previous experiences with discontinuation of long-term benzodiazepine use, where a stepped-care approach was found to be effective. 31A minimal intervention, consisting of an advisory letter or a consultation to discuss discontinuation with the GP proved effective to discontinue benzodiazepines. 32Apparently, the parallel with antidepressants was made too easily, with patients and GPs being hesitant to discontinue.
Of the large number of long-term antidepressant users, only a small portion consented to participate in this study (<15%).Patient recruitment is a known problem, especially in mental health research. 33However, despite the low response rate, the sample size to provide sufficient power for the trial was reached by approaching more practices and patients than originally anticipated.Due to privacy regulations, these long-term antidepressant users remain anonymous until giving consent.Unfortunately, it is not known why patients decided not to participate.It is conceivable that patients who were not willing to participate were more reluctant to change their antidepressant treatment.This would make the study's findings even more concerning as, in those circumstances, the chances are that with a larger, more generalisable population, the percentage of patients successfully discontinuing their antidepressant medication would even be lower.The recruitment success of patients for participation in such an evidence-based intervention could illustrate the difference between perceived self-interest (by the patient) and perceived patient interest (by researchers and practitioners).Further studies about antidepressant discontinuation should therefore focus on patients who are motivated for discontinuation.
Due to the pragmatic nature of this study, the intervention was not imposed on the patients and their GPs.Noncompliance with the given recommendation was found in almost half of the cases.Further qualitative research might be helpful to understand the barriers patients and GPs perceive in discontinuing long-term antidepressant use in patients in remission, and to facilitate the construction of a more effective intervention to reduce inappropriate long-term antidepressant use.

Comparison with the literature
This study showed that many patients reject a proposal to discontinue antidepressant use, that many GPs agreed with the decision not to follow the advice to discontinue and that a large number of patients (32/36) who agreed to follow the protocol failed to do so.Clearly, there is a large gap between what guidelines recommend and what happens in daily practice.Although deviation from a guideline may be consistent with good care, the scale of non-adherence raises another possibility; namely, that apprehensiveness about change and difficulties with discontinuation is much more important than was initially expected.This apprehensiveness about change was found in both patients and GPs.Qualitative research has suggested that patients attribute their wellbeing to the (continued) use of antidepressants.5][36] GPs also perceive barriers to discontinuation, wishing 'not to disturb the "equilibrium" the patient experiences', to 'follow the path of least resistance' and to 'let patients be'. 36GPs operate in a difficult environment: dealing with guidelines, their own fears, patients' opinions and fears, and the difficult process of discontinuation.Adherence to guidelines is difficult.Attempts to discontinue antidepressant use -while very desirable in the light of the huge prescription rates -become a complex task when taking all these factors into account. 37ately, guidelines have become more conservative in their recommendations concerning the prescription of antidepressant medication.It is conceivable that the GPs in the PANDA study did not agree with the recent guidelines.Alternatively, it may be that GPs had to get used to these new insights, with guidelines having previously advocated for increased antidepressant prescription.The prescribing behaviour of GPs is certainly an important topic: they should become more reluctant in prescribing, and should inform patients that the medication will only be necessary for a limited period of time and can be discontinued after being in remission for a period of 6 months.Patients discontinuing their antidepressant medication should also receive more information, guidance and support than they receive at present.In addition to the issue of the difficulty of discontinuing inappropriate antidepressant medication, there are several other reasons justifying a reluctance to prescribe antidepressant medication.Firstly, the evidence of the substantial placebo effect in patients with depression is strong, with the exception of the more severe cases. 38Secondly, the availability of psychological treatments suitable for primary care is growing.Important examples are problemsolving treatment and behavioural activation; both treatments can be delivered by junior mental health workers. 39

Implications for practice
This study demonstrates the difficulty of correcting unnecessary (according to the guidelines) longterm antidepressant use, fuelled by an apprehensiveness regarding change on the part of both patient and GP.A recommendation to discontinue is not effective, and maybe even counterproductive.The authors advocate developing education programmes for GPs, including such topics as GPs' attitudes towards discontinuation, appropriately motivating patients to discontinue antidepressant use, and managing the process of discontinuation.Notwithstanding, it is felt that the first, and possibly most important, step to prevent inappropriate long-term use of antidepressant medication in primary care is to be more restrictive in prescribing antidepressant medication in the first place and make more use of alternative, non-pharmalogical treatments.It might be useful to forewarn patients about the difficulty of discontinuing and to encourage using antidepressants only for a limited period.Regular review could possibly prevent both overtreatment and undertreatment.

Figure 1 .
Figure 1.Flow diagram of practices and participants.Figure 1 continued on next page

Figure 1
Figure 1.Flow diagram of practices and participants.Figure 1 continued on next page

Figure 2 .
Figure 2. Patient flow and outcome in the overtreatment trial.In the intervention group 20/70 patients were lost to follow-up (12 in the group of patients with no intention to comply and 8 in the group with the intention to comply with the recommendation).In the control group 10/76 patients were lost to follow-up.AD = antidepressant.

Table 1 .
Baseline characteristics of participants (inappropriate long-term antidepressant users) in the overtreatment trial at individual level in frequencies, unless stated otherwise.Overtreatment: 9 months antidepressant use, without a current indication for maintenance therapy SD = standard deviation.Eveleigh R et al.BJGP Open ; DOI: 10.3399/bjgpopen17X101265 6 of 11