Mental Health
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Tackling treatmentresistant depression
A step-wise approach is useful for patients who fail to respond to
initial treatment, write Charlene Getty and Declan Lyons
TREATMENT-RESISTANT DEPRESSION is commonly seen
in general practice and may result in significant morbidity and impaired function and quality of life. A patient is
said to be suffering from resistant depression when they
have failed to display an adequate response to two different
antidepressants given in therapeutic doses for an adequate
period of time. An adequate duration for a trial of antidepressant therapy has been defined by some clinicians
as four to six weeks. Others assert that a minimum of six
weeks is required. However, if the patient exhibits a partial
response during the initial period, another four to six weeks
of treatment could be undertaken. Therefore, a total of 10
to 12 weeks may be required in some cases to elicit a full
antidepressant response.
Prevalence
It has been estimated that between 10-30% of patients
with a major depression fail to respond to treatment. With
vigorous treatment, possibly between 10-15% will improve.
However, there still remains between 10-15% of patients
who do not make an adequate response. With this group
of patients you have to wait for a natural remission of the
condition or accept that depression is a condition of high
morbidity, and unfortunately, there may exist a minority who have a poor prognosis and will remain chronically
depressed. Addressing psychosocial factors may be the primary issue here.
Assessment
The first step is to do a complete review of the patient’s
situation to confirm the diagnosis of depression. Factors
that affect treatment-resistant depression are as follows:
• Wrong diagnosis: The diagnosis of depression may be challenging in some people. Most commonly, some forms of
bipolar disorder are misdiagnosed as depression because
manic phases may be less pronounced than depressive
phases. It is also important to rule out another important
condition such as schizophrenia, personality disorder or
early dementia
• General medical conditions: Other medical conditions
can sometimes mimic or worsen depression. These
include hypothyroidism, anaemia, chronic pain and heart
problems. Therefore, it is important to rule out these conditions for effective management of resistant depression
• Psychiatric comorbidity such as substance misuse, eg.
alcohol and illicit drugs, can also worsen the outcome of
a depressive disorder
• Psychosocial stressors: If a patient is under constant stress
in their everyday life – such as relationship trouble, financial instability, inadequate housing or a history of childhood
abuse or neglect, which can continue to affect the patient
into adulthood – medication alone may not be successful
• Non-compliance with medication: This is a major problem. Approximately one-third of patients do not get the
prescription they are offered. They may see medication as
inappropriate treatment for their depression. Those who
commence treatment often do not take the medication
on as regular a basis as is necessary. A further proportion
fail to take the full therapeutic course, stopping before
it has time to act. Many also stop the medication due to
the side-effects they experience in the first few days after
commencing the drug.
A good doctor-patient relationship and time spent with
the patient to understand their needs and expectations is
crucial to minimise non-compliance.
Treatment strategies
When discussing the various treatment options with
the patient, it is first important to establish how long
the depression has been present, its nature and course,
and previous treatments used. Often, patients may have
improved to some extent, which may be relevant if major
changes in managing the condition are needed.
General measures
Psychotherapy in the form of supportive listening, reassurance and education is required for every patient to
ensure that they do not become demoralised and pessimistic. Inform the patient of the treatment plan and inform
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Table 1
Strategies for treatment-resistant depression*
Optimisation
Maximise dose/serum level
Substitution – changing from one antidepressant to another
• SSRI to TCA or MAOI, or atypical antipsychotic
Combination – adding another antidepressant from another
class
• SSRI + TCA, TCA + MAOI, SSRI + atypical antidepressant,
SSRI + buspirone
Somatic therapies
• ECT, VNS, rTMA, light therapy
Augmentation – adding a second agent that is not an antidepressant but may enhance the antidepressant effect
• SSRI or TCA to Li, T3, atypical antipsychotic, stimulant,
hormone, pindolol, anticonvulsant, DA angonist
SSRI = selective reuptake inhibitor; TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor; ECT = electroconvulsive therapy; VNS = vagusnerve stimulation; rTMS = repetitive transcranial magnetic spectroscopy; DA = dopamine
*Adapted from Gotto J, Rapaport M. Primary Psychiatry. 2005; 12(2)
antidepressants if one fails. It also emphasised equally
good response rates in switching from one SSRI to another,
versus switching to a different class of antidepressant.3
Combination strategies
Different classes of antidepressants are prescribed at the
same time to achieve greater effect by targeting several
neurotransmitters at once.
• SSRI and bupropion/buspirone: The STAR*D study found
that 30% of patients who combined citalopram with either
bupropion or buspirone became symptom-free. Those who
added bupropion experienced fewer side-effects and a
slightly better reduction of symptoms than buspirone3
• SSRIs and TCAs: A study comparing combination treatment with fluoxetine and desipramine versus fluoxetine
alone over a four-week trial showed that 71% of patients
on combination therapy achieved remission versus only a
few on monotherapy becoming symptom-free at the end
of four weeks.3 It is also shown that combining with a TCA
reduces the time taken to go into remission5
• SSRIs and mirtazapine: A study carried out that added
mirtazapine to SSRI-resistant patients resulted in a 55%
response6
• MAOIs and TCAs: Widely used in the 1960s. However,
there is potential for severe drug interaction.
Whenever drugs are combined, they should be titrated
slowly, monitoring for drug interaction.
Augmentation strategies
This involves adding a second agent that is not regarded
as an antidepressant when there is partial response to the
antidepressant. Examples of second agents include:
• Lithium: Data from randomised trials show that lithium can
be effective in resistant depression. Approximately half of
depressed patients show response in one to three weeks. It
can be added to any primary antidepressant regimen with
good effect. However, caution is advised with SSRIs and
SNRIs as there is a risk of serotonin neurotoxicity. Start at
a low dose of 250-400mg and increase slowly, monitoring
plasma levels to maintain between 0.5-0.8mmol
• Thyroid hormone (tri-iodothyronine and T3): There is evidence that augmentation of TCA with T3 is effective, with
augmentation therapy with T3 increasing the response by
60% in treatment resistant depression7. There is less evidence available for augmentation of SSRIs with T3. The
usual dose used is 20-50µg per day. Thyroid function
tests are required prior to administration but should not
be used in patients with cardiac history
• Atypical antipsychotics: In non-psychotic depression, con-
ventional antipsychotics are of little value. However, there
is promising evidence that some atypical antipsychotic
drugs may have an antidepressant effect when used in
combination with SSRIs.
With regard to olanzapine, a randomised controlled trial
showed that for patients resistant to fluoxetine treatment,
the addition of olanzapine at 5-20mg produced a significantly greater response than a placebo or olanzapine
monotherapy. Improvements occurred within one week.
Open studies also support the use of low-dose risperidone
augmentation in SSRI-resistant depression.9
Electroconvulsive therapy (ECT)
If severe depression persists, ECT should be considered. ECT is often beneficial to patients who have failed to
respond to antidepressants and is probably more effective
in the most severe depression, or depression with psychotic
features. Trials of ECT report high response rates of about
80%. However, the presence of medication resistance
decreases the likelihood of a response to ECT.
Relapse rates post ECT are approximately 50% at one
year post treatment, therefore, adequate drug treatment is
required post ECT treatment. ECT can be used at any point
in the treatment of resistant depression, including after
the onset of symptoms of severe depression with suicidal
intent, and after the onset of psychotic symptoms and psychomotor retardation.
Step-wise approach
The management of patients with depression who have
failed to respond to antidepressant treatment is a common
problem and in the primary care setting, GPs have a role to
play in identifying and treating such patients. Therefore, it
is important for GPs to have confidence in their ability to
manage the pharmacological aspects of treatment-resistant
depression. A step-wise approach is useful, and GPs should
always be mindful of what their next step should be if the
current step fails.
It is important to believe that the patient can improve and
not to become frustrated by their apparent lack of response.
But even with aggressive therapy, a proportion of patients
with treatment-resistant depression will achieve palliation
rather than cure, and with these people, ongoing support,
encouragement and psychological treatment has a life-sustaining function.
Charlene Getty is a registrar and Declan Lyons is a consultant
psychiatrist at St Patrick’s Hospital, Dublin
References on request
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them of their responsibility for persevering with treatment
and taking part in everyday life activities. Cognitive behavioural therapy (CBT) is one of the principal psychological
therapies utilised in depression.
Medication
The main pharmacological treatments involve:
• Dose optimisation
• Switching antidepressants
• Combination strategies
• Augmentation strategies
• Electroconvulsive therapy (ECT).
Dose optimisation
When reviewing a patient’s history, if no additional clinical information is revealed, then current antidepressants
should be continued at increased doses if possible. For
example, many patients taking tricyclic antidepressants are
treated at relatively low doses and may benefit if the dose is
increased to 150-200mg per day. Plasma monitoring of tricyclic levels is required at higher doses to exclude toxicity.
Also, ECGs should be monitored in patients with a previous
cardiac history.
Venlafaxine also has greater efficacy in higher doses and
therefore should be increased for improvement of symptoms. However, selective serotonin reuptake inhibitors
(SSRIs) have a relatively flat dose response curve. But if the
patient has shown partial response and tolerability allows,
the dose should be increased.1
Switching antidepressants
If a patient does not respond to one antidepressant, then
a different preparation should be tried. There is evidence
that switching to another class of antidepressant can produce benefit in about 50% of patients who are unresponsive
to initial medication.2
Using a different class
Different class options that are available to patients who
have not received maximum benefit from treatment with an
SSRI include:
• Venlafaxine – the serotonin and noradrenaline reuptake
inhibitor (SNRI) that has been most extensively studied
• B upropion – enhances noradrenaline and dopamine
neurotransmitters
• Trazodone – partial serotonin agonist (5HT) activity
• Duloxetine – inhibits reuptake of both serotonin and
noradrenaline
• Mirtazapine – acts on noradrenaline and serotonin through
alpha 2 and 5HT1a receptors
• Tricyclic antidepressants (TCAs)
• Monoaminoxidase inhibitors (MAOIs).
Therefore, recruiting different neurotransmitter systems in
an attempt to treat the depressive disorder can be useful.
Switch to a different antidepressant in the same class
Switching to a different antidepressant in the same class
can be effective. For example, if the SSRI citalopram does
not work, then switching to sertraline may yield benefit.
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study – the largest and longest study for
depression treatment – found that 25% of patients who
switched from citalopram to either sertraline, venlafaxine,
or bupropion became symptom-free. This positive result
was similar within the three treatment groups.
The STAR*D study highlighted the benefit of switching
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