In Ireland, depression affects 7.7% of the population, while one in four people will experience depressive symptoms necessitating a clinical intervention at some point in their lives.¹

Treatment-resistant depression (TRD) is a challenging problem commonly faced by practising psychiatrists. Patients suffering from TRD are at high risk of relapse of depressive illness, suicide and increased healthcare utilisation.² The most widely accepted definition of TRD is a major depressive episode that does not respond satisfactorily to two adequate trials of antidepressants of different classes. Adequate trial means that an adequate dose and duration of antidepressant has been utilised.

The Sequenced Treatment Alternative to Relieve Depression (STAR*D) study provides the main evidence for the categorical definition based on two treatment failures. In the STAR*D study 3,671 patients who presented with major unipolar depression were prospectively administered up to four sequential trials of pharmacotherapy.³ The rate of remission appeared to be comparable for the initial and second course of treatment (37% and 31%), and then the rate of remission significantly declined for the third and fourth steps of treatment to 14% and 13% respectively.

Response to treatment in depression is classified according to the amount of improvement from baseline on the depression rating scale. An improvement of < 25% means no response. Partial response is an improvement of 25-49%. A response is an improvement of > 50%. While remission is a depression rating scale score less than or equal to a specific cutoff that defines the normal range for the depression rating scale.

Before making a diagnosis of treatment-resistant depression, consideration should be given to rule out other psychiatric diagnoses such as an anxiety disorder, dysthymia, a personality disorder, an adjustment disorder, and alcohol or drug abuse. It is also important to ensure that there is no underlying medical disorder, for example, Parkinson’s disease, adrenal insufficiency, multiple sclerosis, dementia, malignancy or a thyroid disorder.

Consideration should also be given to identify and manage risk factors that can affect the treatment outcome, such as ischaemic heart disease, chronic pain or certain medications, for example interferon and glucocorticoids. Psychosocial stressors, eg. adverse life events, inadequate social support and lack of proper routine, can also affect response to treatment. 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.

Management of TRD

Once a correct diagnosis of TRD is made the management options are broadly divided into three categories. Biological treatment, psychotherapy and electroconvulsive treatment. It is important to be aware of the multiple treatment options for treating depression, including the different classes of antidepressants, augmentation agents, psychotherapeutic interventions and social support networks. Educating patients and giving them information on other available treatment modalities like ECT is also of vital importance.

Pharmacological treatments

The STAR*D Study, completed in 2006 in the US, and funded by the National Institute of Mental Health provides much of the evidence on treatment of major depressive episodes. The main aim of this study was to assess the effectiveness of antidepressant medications in treating major depression.³

According to this trial SSRIs are the first line of treatment for major depressive episode. They offer the most benefit with the least amount of side-effects. Citalopram  or escitalopram are the typical first line of antidepressants used. If there is no response to the first line of treatment, patients can either be switched to a different class of antidepressant or have their first antidepressant augmented with another class of antidepressant. 

A variety of options are available to replace the first line of antidepressants. Switchover should be done cautiously. Depending on the class of antidepressant, switchover can be done either by stopping and starting the new medication, slow cross-tapering or stopping the first antidepressant and waiting for a washout period and than starting the new medication. The most commonly used second line antidepressant is venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI). 

An atypical antidepressant, for example mirtazapine, can also be used, which is also helpful in depression-related insomnia. Similarly patients who want to avoid the sexual side-effects associated with most antidepressants may be prescribed bupropion, which is less likely to cause these side-effects.

Tricyclic antidepressants such as amitriptyline, doxepin, nortriptyline or MAOI for example phenelzine, tranylcypromine can also be used, but they are not initially used because of their side-effect profile and are especially dangerous in overdose. 

A meta-analysis compared switching from SSRI to venlafaxine or another SSRI. It showed that more patients achieved remission when switched to venlafaxine from SSRI as compared to those who were switched to another SSRI.⁴

Augmentation of an antidepressant, which did not show an initial response with another class of antidepressant is acceptable. There has been no established difference between augmentation and switching to another class of antidepressant.

If the patient has partial response from the initial antidepressant and is tolerating the medication well, augmentation should be the first line of management. Augmentation agents include low dose antipsychotics like quetiapine, olanzapine, and sulpiride. Lithium or other augmentation agents like bupropion, mirtazapine, buspirone and triiodothyronine can be used. 

Most of the second generation antidepressants are roughly equivalent in their efficacy, therefore, they are prescribed considering factors such as the patient’s previous response to treatment, patient specific symptoms, side-effect profile, other medications the patient is taking, patient preference and cost of the medication.

In the STAR*D trial it has been shown that 67% of patients who failed to respond to first line treatment eventually achieved remission after up to four courses of treatment. However, lack of social support and other co-morbid psychiatric disorders like prominent anxiety symptoms can negatively affect prognosis.

Psychotherapy

Psychotherapy can be an effective alternative to antidepressants in mild to moderate depression. It may also be employed as an augmentation therapy in treatment resistant depression. Different modalities of psychotherapy can be used, for example cognitive behavioural therapy and interpersonal therapy. Multiple randomised control trials have shown cognitive behavioural therapy to have benefit in treatment resistant depression if combined with an antidepressant. 

A one-year randomised trial compared CBT (12 to 18 sessions) plus usual care with usual care alone in 419 outpatients with treatment resistant depression. Remission occurred in more patients who received CBT plus usual care than usual care alone (28% versus 15%).

A 12-week randomised trial compared citalopram plus CBT with citalopram plus adjunctive pharmacotherapy in 182 outpatients who did not respond to citalopram monotherapy. The number of patients who achieved remission was comparable (23% and 33%).⁵ Exercise, psycho-education of patients and their family on symptoms of depression and exploring the social supports available to them is also very important. 

The services of various organisations can be extremely helpful if utilised properly. Aware (www.aware.ie) offers a range of services including information, education and formal supports such as their 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.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is an effective treatment for patients with major depression and can be considered first-line for patients with severe treatment-resistant depression, which has not responded to other modes of treatment.⁶ It is not available in all psychiatric hospitals in Ireland. 

Over a period of years ECT treatment has become more refined with improved side-effect profile and does not have any effect on long-term memory. There is still an unjustifiable negative perception of ECT in the general public, mainly because of the lack of awareness and knowledge of the treatment. ECT usually involves eight sessions of treatment. ECT has also been adapted to be administered unilaterally as opposed to the traditional bilateral treatment, this being associated with few cognitive side-effects.

Conclusion

Depression is a common psychiatric condition and the incidence is rising. One in four will have depression in their lifetime. Early recognition and treatment intervention in the form of social support, psycho-education, psychotherapy and pharmacotherapy based on the requirement of the patient is vital.

Treatment-resistant depression can be challenging both in primary care and the specialist psychiatric setting. Correct diagnosis and out ruling other psychiatric and medical conditions is the first step in proper management of TRD.

Patients should be supported throughout with regular follow-up. Compliance with treatment and minimising risk of suicide or self-harm are important management goals. 

For the physician it is important to utilise resources available to them and remain up-to-date on the latest research and advancements in managing treatment resistant depression.

References

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. Arch Gen Psychiatr 2005; 62(6):617-27
2. Souery D, Papakostas GI, Trivedi MH. Treatment-Resistant Depression.J Clin Psychiatr 2006; 67(suppl 6):16-22
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. Am J Psychiatr 2006; 163(11):1905-1917
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. J Clin Psychiatr 2006; 67(12):1836-1855
5. Wisniewski SR, Fava M, Trivedi MH et al. Acceptability of second-step treatments to depressed outpatients: a STAR*D report. Am J Psychiatr 2007; 164(5):753-760
6. Lisanby SH. Electroconvulsive therapy for depression. New Engl J Med 2007; 357(19):1939-1945