Standard current prescribed treatment
GPs manage the vast majority of depressive illness in the community and will be dealing with prescribing in depression in adults on an almost daily basis. The prescribing of antidepressants in general practice is indicated in moderate to severe depression and in sub threshold depression that has persisted for more than two years. It is also to be considered in mild depression if there is a history of moderate to severe depression the past.
We are all used to our prescribing options being at least guided by local commissioning group medicine management teams and prescribing support software. Citalopram 20mg and Sertraline 50mg will often be the first line drugs we are recommended. They represent the best balance between cost and efficacy currently and should be first-line treatment if there are no contraindications or history of adverse events. One meta-analysis however found Escitalopram to be the most effective and cost effective.1 As with all prescribing the patients ideas about treatment should be explored and fears of dependency allayed. Ensuring common side effects are discussed prior to initiation and a set plan for when reviews will occur and step ups or switching of treatment occur increases compliance and success.
The QOF depression targets may seem frustrating at times but they are supporting good clinical practice and reflect what most GPs do routinely. A risk assessment of self-harm should be performed at the start of treatment, and a review of tolerability and effectiveness should occur around two weeks.
If a partial response occurs at four to six weeks and the drug is being tolerated and taken correctly, this should trigger a step up of medication strength in line with the summary of product characteristics, or switching to another type of antidepressant if the patient prefers or there are side-effects.
A persistent lack of response to treatment should lead to a review of diagnosis, checking concordance, and stepping up the NICE stepped care model, engagement with secondary care and consideration for augmentation of medication. We should consider social and employment factors, would befriending or employment support programs be beneficial? Concomitant drug or alcohol use should be screened for and addressed.2,3
What’s newly available
As most jobbing GPs will be aware, there has not been much change in the therapeutic options available to us over the last few years.
Duloxetine has a license for depression and may have a new niche for treatment of depression with co-existing neuropathic pain. If patients are on amitriptyline for neuropathic pain, adding in an SSRI is not advised as it can lead to the tricyclic antidepressant not being metabolised and can cause toxic levels. Options for the management of depression in patients with high levels of neuropathic pain could be duloxetine and venlafaxine. Research has shown that depressed patients are three times a likely to have chronic pain and that baseline level of chronic pain has an impact on response to treatment of depression at six months.4
The antipsychotics quetiapine, olanzapine and aripiprazole are not new drugs but have a new role in augmentation of antidepressant therapy in secondary care now.5
Augmentation strategies using T3, modafinil and lamotrigine are being used in refractory depression, but again under specialist care. They are drugs that we may see on letters from our secondary care/tertiary care colleagues, however, and potentially continuing on repeat prescriptions under a care plan.
Agomelatine is a melatonin receptor agonist and selective serotonin receptor antagonist that is being used in specialist centres. It has a similar efficacy to other antidepressants but can be tolerated when other treatments are not. It requires monitoring of liver function and is considered third-line therapy and for specialist initiation only.
The combination of mirtazapine and SSRI is a more frequently seen augmentation strategy and is probably the safest options of antidepressant combination, but further research is required.2,6
What has fallen out of fashion and why?
NICE guidelines state quite clearly that we should not use dosulepin, as the side-effects and toxicity outweigh meager benefits. We should be considering this at medication reviews.
The risks of tricyclic antidepressants in overdose means that they are not favoured except for lofepramine, which can be a useful option in the appropriate scenarios.
Paroxetine has fallen out of favour due to its risk of drug interactions and high discontinuation symptoms.
The non-reversible MAOIs should remain a prescription for the specialists to initiate.
Special cases and their treatment
We are still not able to meaningfully subtype depression into classifications to which we can target therapy or predict response to therapy.
The tailoring of treatment is really the recognition of potential drug interactions and clinical scenarios where the side-effect profiles of antidepressants could be dangerous. As GPs, we are rarely managing patients with single pathologies and the problem with guidelines is they get complicated quickly in patients with significant comorbidity. Depression is more prevalent in patients with chronic diseases. As my prescribing support software frequently points out to me, there are specific situations we need to watch.
- One of the most common drug groups that can interact with SSRI standard therapy are the NSAIDs. When used in combination they can increase risk of gastrointestinal bleeding. Consider mirtazapine or PPI cover for SSRI in patients who need NSAIDs to continue.
- In liver disease, consider initiating treatment at lower doses.
- Depression in chronic heart disease is common and tricyclic antidepressants should be avoided due to potential side-effects.
- In general, sertraline and citalopram remain the NICE-recommended treatment of depression in patients with significant comorbidity.
- Avoid SSRIs with triptans as this can cause serotonin syndrome.
- Fluoxetine is the antidepressant with best evidence for use in pregnancy and sertraline is the best in breastfeeding mothers. Specialist opinion is recommended in the management of depression in these groups.
- Management of depression in those over 65 does not differ from other patients. Improvement of symptoms can start about a week later than those under 65. Patients on tramadol and oxycodone started on SSRIs are at risk of serotonin syndrome.7
- Postural hypotension can be more pronounced with SSRIs in those over 65, and one study found a 66% increased risk of falls when compared to those not on SSRI.9,10
- Blood pressure monitoring should be performed in venlafaxine use.
- Consider an ECG in patients with cardiac disease prior to initiating citalopram or Escitalopram to exclude any QT interval lengthening.
Assessment of response to standard SSRI therapy can lead to some tailoring of ongoing therapy. If the patient is found to have had sexual dysfunction, agitation, insomnia or nausea as side-effects at review, mirtazapine may be a better drug for their depression. If they were found to have significant blunting of affect following treatment with SSRI, lofepramine may be better suited to them.12
Development of hypomanic symptoms on SSRI must immediately raise the possibility of a bipolar depression rather than unipolar depression diagnosis. Screen for history of hypomanic and manic symptoms at time of initiation of treatment.
The time at which medication is to be withdrawn should be tailored to the individual as well. In the first episode of depression, treatment can be stopped six months after adequate response, but if there is a history of recurrent or severe depression then treatment should be slowly withdrawn after continuation for two years. Rate of withdrawing medication should be adjusted to length and dose of treatment too.
There has been a trend of using mirtazapine in patients with insomnia predominant in the presentation. Insomnia is a common aspect of depression and often treatment of depression with standard therapy improves insomnia as depression resolves.
Non-drug options and their evidence base
Cognitive behavioural therapy (CBT) remains a vital element in the treatment of depression and has high levels of evidence to back it up. NICE recommend the use of low intensity psychosocial interventions or group CBT for NICE step 2 (persistent subthreshold or mild to moderate depression) in patients with no chronic physical health problems, and low intensity psychosocial intervention in those with chronic physical health problems. A low intensity psychosocial intervention can include guided self-help, a structured group exercise program or computerised CBT. Psychological therapy should be part of treatment in all steps above 2.
Behavioural couples’ therapy is currently in NICE guidance for depression. Interpersonal therapy is another modality with a good evidence base that may allow some tailoring of psychological therapy to the patient. Mindfulness may also be useful for patients with recurrent depression currently in remission.
St John’s Wort is commonly used as over the counter medication for depression. NICE recommend that it is not advised for patients or prescribed due to large variations in dose in different preparations and potential interactions with other medications (oral contraceptives, anticonvulsants and anticoagulants).
Electroconvulsive therapy is indicated in severe and resistant depression.
Dr Tom Shackleton is a GP mental health lead for CamHealth LCG.
Dr Shackleton would like to acknowledge Dr R. Hamish McAllister-Williams, reader in clinical psychopharmacology and consultant psychiatrist, for his talk on depression given at the Pulse Mental Health Seminar 2014.
1 Ramsberg J, Asseburg C, Henriksson M. Effectiveness and cost-effectiveness of antidepressants in primary care: a multiple treatment comparison meta-analysis and cost-effectiveness model. PLoS One, 2012;7(8):e42003.
2 Haddad PM, Talbot PS, Anderson IM, McAllister-Williams RH. Managing inadequate antidepressant response in depressive illness. British Medical Bulletin
3 NICE. CG90: Depression in adults. London: NICE; 2009
4 DeVeaugh-Geiss AM, West SL, Miller WC et al. The adverse effects of comorbid pain on depression outcomes in primary care patients: results from the artist trial. Pain Medicine, 2010;11:732–41
5 Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry, 2009;166:980-91
6 Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry, 2002;51:183-8
7 Mark TL, Joish VN, Hay JW et al. Antidepressant use in geriatric populations: The burden of side effects and interactions and their impact on adherence and costs. Am J Geriatric Psychiatry, 2011;19:211-21
10 Coupland C, Dhiman P, Morriss R et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ, 2011;343:d4551.
11 Hatcher S, Arrol B. Newer antidepressants for the treatment of depression in adults. BMJ, 2012;344:d8300
12 McAllister-Williams & Yates in ABC of Anxiety and Depression. Gask and Chew-Graham, Wiley; 2014