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Continuing education - Brain disease - Management of treatment resistant depression

Many patients who do not respond to initial treatment for depression will subsequently find remission when prescribed alternative or supplemental antidepressants, write Clare Shields and Declan Lyons

Mental illness affects one in four people in their lifetime.1 Mood disorders are the most common mental illnesses and depression is the fourth highest cause of disability worldwide. It is an extremely common presentation to primary care with only upper respiratory tract infections and hypertension presenting more frequently.2

A significant number of people with depression do not respond to the initial treatment. In one trial, only 37% of patients obtained remission with citalopram (a selective serotonin reuptake inhibitor – SSRI) alone.3 Treatment-resistant depression does not have a standardised definition but is widely considered to be a failure to respond satisfactorily to two trials of antidepressant monotherapy.

It is important to be aware of the steps in the treatment plan for depression, including the different antidepressant classes and augmentation agents, the availability and benefits of psychotherapy, and the social supports surrounding the patient. It is also vital to educate and give appropriate information about the treatment options available, such as electroconvulsive therapy (ECT), if a patient requires inpatient care and treatment.

Important considerations
When making a diagnosis of treatment-resistant depression, it is important, firstly, to establish if the diagnosis of depression is correct. Other psychiatric diagnoses such as anxiety disorders, dysthymia, personality disorders, adjustment disorders and alcohol and drug abuse should be ruled out. It is also important to ensure that there is no underlying medical disorder, for example, Parkinson’s disease, multiple sclerosis, dementia or thyroid disorders.

The importance of compliance to medications should be explored with patients and they should be prescribed an adequate trial of an antidepressant. This would usually be for six to 12 weeks, however, if there is little response after four to six weeks, it is advised to move to the next treatment step.

Biological treatment
The STA R*D trial, (Sequenced Treatment Alternatives to Relieve Depression), which was a collaborative study on the treatment of depression, completed in 2006 and funded by the National Institute of Mental Health in the US, provides much of the evidence and information on the treatment steps in the management of depression.3

According to this trial, the first choice in the treatment of depression is an SSRI. A typical choice would be citalopram 20mg or escitalopram 10mg. If a patient does not respond to the initial antidepressant or cannot tolerate it, it is recommended to switch antidepressant class. When switching class, you should taper and then stop the initial antidepressant and start the new medication.

There are many choices available when switching antidepressant class. The most commonly prescribed would be the serotonin-norepinephrine reuptake inhibitor (SNRI), venlafaxine, followed by atypical antidepressants such as mirtazapine and bupropion.

Tricyclic antidepressants such as amitriptyline and dothiepin are less commonly prescribed and tolerability issues, often arising from anticholinergic side-effects, may be relevant. Monoamine oxidase (MAO) inhibitors, for example, phenelzine, are another option.

The role of venlafaxine when switching from an SSRI is well researched. A meta-analysis compared switching from an SSRI to another SSRI or to venlafaxine. It found remission was obtained in more patients who received venlafaxine than a different SSRI.4

Changing to atypical antidepressants from an SSRI shows similar efficacy to switching to another SSRI.5

If a patient is tolerating the antidepressant well and has some symptom relief but it is not yet satisfactory, augmentation is recommended as first-line management. Augmentation agents include second generation antipsychotics such as quetiapine, aripiprazole and olanzapine. Lithium or a second antidepressant, for example, mirtazapine or bupropion can also be prescribed. Other agents include buspirone and triiodothyronine.

There is little difference in the efficacy of these medications,3 therefore, it is important to take into account the past medical history of the patient, their previous treatment record, patient preference and cost, safety, side-effects and interactions of the medications when prescribing. It is also reasonable to switch antidepressant in this scenario.6

It is accepted too that augmentation of an antidepressant that has not had any effect can be tried as first-line rather than switching class. In both cases there is little difference in the outcomes between switching and augmentation in treatment-resistant depression.7

The STA R*D trial has shown that 67% of patients who fail to respond to an initial course of citalopram will achieve remission with up to four courses of successive treatment. Prognosis is worse for patients with prominent anxiety symptoms or a comorbid anxiety disorder. Lack of social support also negatively impacts on patients.

Psychotherapy may be employed as an alternative to medication in mild to moderate depression and can be useful in severe depression in combination with medications. It is particularly beneficial for relapse prevention. Models of therapy include cognitive behavioural therapy or interpersonal therapy. However, the availability of psychotherapy is frequently a limiting factor.

Research has also shown that psychotherapy is more successful in certain patient groups. This includes patients with higher levels of education and patients who have a family history of mood disorders.8 A 12-week study compared CBT to an antidepressant (venlafaxine, bupropion or sertraline) in patients who did not obtain symptom relief with citalopram. It showed similar rates of remission with both treatments. Similar numbers also stopped each treatment due to side-effects or incompatibility.8

Social supports
It is important to explore with patients the social supports available to them including family and friends. Education regarding depression and its symptoms is also vital for patients and their families.

Organisations such as Aware (www.aware.ie) offer a range of services including information, education and formal supports such as Aware’s Life Skills programme. Patients and families can access these services online or can participate in support meetings through the nationwide network of local groups.

Other useful services include the crisis support agency, Samaritans (www.samaritans.org) and Pieta House (www.pieta.ie), an organisation with multiple locations around the country, which helps to prevent suicide and self-harm.

Referral and ECT
If the above treatment steps have failed, referral to a psychiatrist should be considered. It is recommended for patients who do not respond to between two and four treatment trials. Referral is also required if psychosis, suicidal ideation or catatonia are present.

One treatment available if the patient is admitted to hospital is ECT. It can be particularly useful in patients with psychotic depression and is first-line when persistent suicidal ideation is present, there is dehydration or weight loss due to refusal to eat or malignant catatonia.9

It is the most effective treatment in patients with major depression and can be considered first-line for patients with severe treatment-resistant depression.10 Six to eight treatments are usually required to achieve remission and two treatments are typically given per week. It is not available in all psychiatric centres in Ireland.

ECT has perhaps an unjustifiably negative public image, focusing particularly on concerns about adverse effects on cognitive function. However, it has not been shown to have an effect on long-term cognition.

Depression is a very common presentation, affecting one in four people in their lifetime. It is important to regularly review affected patients in relation to symptoms and side-effects of the medications. We need to emphasise the importance of persisting with treatment trials. These patients require reassurance that they will not be abandoned and they should be encouraged to have faith in the treatment.

Treatment-resistant depression can be challenging to manage and healthcare professionals need to draw on all the resources available to them and remain up to date regarding the latest developments in the management of this condition.

Clare Shields is a psychiatry registrar and Declan Lyons is a consultant psychiatrist at St Patrick’s Hospital, Dublin


  1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of general psychiatry. 2005;62(6):617-27
  2. Cooke G, Valenti L, Glasziou P, Britt H. Common general practice presentations and publication frequency. Australian family physician. 2013;42(1-2):65-8
  3. Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. The American journal of psychiatry. 2006;163(11):1905-17
  4. Ruhe HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. The Journal of clinical psychiatry. 2006;67(12):1836-55
  5. Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine- XR after failure of SSRIs for depression. The New England journal of medicine. 2006;354(12):1231-42
  6. Fang Y, Yuan C, Xu Y et al. Comparisons of the efficacy and tolerability of extended- release venlafaxine, mirtazapine, and paroxetine in treatment-resistant depression: a double-blind, randomized pilot study in a Chinese population. Journal of clinical psychopharmacology. 2010;30(4):357-64
  7. Fang Y, Yuan C, Xu Y et al. A pilot study of the efficacy and safety of paroxetine augmented with risperidone, valproate, buspirone, trazodone, or thyroid hormone in adult Chinese patients with treatment-resistant major depression. Journal of clinical psychopharmacology. 2011;31(5):638-42
  8. Wisniewski SR, Fava M, Trivedi MH et al. Acceptability of second-step treatments to depressed outpatients: a STAR*D report. The American journal of psychiatry. 2007;164(5):753-60
  9. Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in treatment-resistant depression. The American journal of psychiatry. 2012;169(12):1238-44
  10. Lisanby SH. Electroconvulsive therapy for depression. The New England Journal of Medicine. 2007;357(19):1939-45
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