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resistant depression-NH2/SS
25/06/2007
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When patients don’t
respond to treatment
Recurrent depressive disorders is a problem often seen by
GPs, write Daniel White and Patricia Casey
GPs IN IRELAND are often the first medical professionals to
assess and treat patients suffering with depression. Outside
specialist psychiatry services, GPs are the main providers of
continuing care for patients experiencing recurrent depressive disorders.
Despite the effectiveness of pharmacotherapy in treating
depressive illnesses, 20% of patients do not respond and up
to 30% only partially respond to a course of antidepressant
medication.1
The principal objective of this article is to inform GPs of
the current approach to the management of depressed
patients who do not respond to pharmacotherapy.
Definition
The term ‘treatment-resistant’ is used to
describe a depressive episode that has failed to
respond to adequate trials of two different
antidepressants.2 A review of the literature
shows that an arbitrarily accepted definition
of an adequate trial is an antidepressant
given at a recognised therapeutic dose for a
period of four to six weeks.1,2,3
There are a number of reasons why patients
do not respond to antidepressants. Adherence to the prescribed agent is an obvious
but important factor. Up to 60% of
patients are non-adherent to antidepressant medications.4
Intolerable
side-effects, inadequate education or concerns over the addictive potential of antidepressants
may all reduce patient adherence. Additionally, the stigma
of mental illness may affect the patient’s willingness to take
antidepressants. In such cases it is appropriate to discuss
these issues with the patient and provide reassurance and
education where possible.
Adjustment disorders resulting from significant changes
in a patient’s life may result in emotional distress and be
mistaken for depressive illness. These symptoms usually
resolve with the passage of time or changes in the patient’s
circumstances and the prescription of antidepressants is
unlikely to be helpful. Psychosocial factors within the home
or at work can also have a profound effect on mood and can
play an important role in the perpetuation of a depressive
illness.5 Co-morbid alcohol and substance misuse can cause
depressive symptoms. Patients using illicit drugs such as
cannabis commonly present with a mixture of affective and
anxiety symptoms or an ‘amotivational syndrome’; which
often resolve after a period of abstinence.6 Additionally, pre-
scribed medications such as beta blockers and isotretinoin
have also been associated with depression.7,8,9
Organic conditions presenting with depressive symptoms
should be considered in any patient failing to respond to an
adequate trial of an antidepressant.9 Anaemia may cause
fatigue, poor concentration and depressed mood. Patients
with endocrine disorders such as hypothyroidism and Cushing’s disease often experience secondary mood
disturbances, as do patients with neurological diseases such
as Parkinson’s disease and multiple sclerosis. In the elderly,
dementia commonly presents with depressive symptoms in
the initial stages of the illness, which resolves as the dementia progresses.1 It is therefore important that
appropriate physical examination and
investigation is performed in all patients
with refractory depressive illnesses.
Therapeutic dose
According to the National Institute of
Clinical Excellence (NICE) guidelines
for the treatment of moderate to
severe depression, a selective
serotonin reuptake inhibitor (SSRI)
should be used as first choice in the
treatment of depression.
Antidepressants should be titrated to a
recognised therapeutic dose and efficacy
assessed after a period of four to six weeks.
If there has been no improvement, or improvement has only been partial, then the antidepressant dose
should be increased and the patient reassessed in a further
two weeks.2 If the patient is unable to tolerate the antidepressant or has no benefit from it, then it should be stopped
and an antidepressant from another class commenced.
Venlafaxine prescribed at higher doses (greater than
200mg), has been recommended by NICE for the treatment
of resistant depression.
Blood pressure should be monitored regularly. Side-effects
such as nausea and vomiting and discontinuation reactions
are more common when venlafaxine is prescribed at higher
doses.
Adding on
The following therapeutic regimens are not usually undertaken by GPs; however they have been included to provide
general practitioners with information on the different pharmacological strategies used by psychiatrists.
Patients who only achieve a partial response to an adequately trialled antidepressant may benefit from adding in
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Mental Health
lithium or tri-iodothyronine. It should be noted that there are
increased risks of side-effects, drug interactions and patient
non-adherence with polypharmacy.
Lithium is the most extensively studied augmentation
strategy for treatment-resistant depression and can be
added to all antidepressant groups. Meta-analyses have
demonstrated the efficacy of lithium over placebo (45% v
18%) and open and controlled studies have shown that
approximately 50% of patients respond to lithium augmentation within four weeks.10 Lithium augmentation should
therefore be considered first-line in patients with treatment
resistant depression.
There are also a number of small studies that have examined the addition of tri-iodothyronine to antidepressants.
The evidence for the efficacy of tri-iodothyronine as an augmenting agent in treatment resistant depression is
questionable,11 and this is now reserved for the most
severely ill, treatment resistant patients.
Combining agents
A number of small studies have examined the efficacy of
combining two antidepressants.12,13,14 It should be noted
however, that the combining of two antidepressants is not
currently licensed in Ireland.
One study has demonstrated significant clinical response
rates in patients with treatment resistant depression to a
combination of venlafaxine and mirtazapine. 12 Clinical
response to this combination occurred with moderate to high
doses of both agents (venlafaxine at doses of at least 225mg
and mirtazapine at doses of at least 30mg). The author of
this study suggests that mirtazapine 15 mg be added in and
titrated up to 45mg once a patient has been established on
venlafaxine 225mg. The most common side-effects
observed were headache, weight gain and sedation.
Although venlafaxine and mirtazapine have minimal pharmacokinetic interactions with each other, the potential for
seizures and cardiac effects may be additive and there have
been reports of serotonin syndrome 15 and spontaneous
haemorrhages.16
Another study demonstrated efficacy and safety in combining specific serotonin reuptake inhibitors (SSRIs) with
mirtazapine.14 The researchers in this study examined the
effect of adding mirtazapine to treatment resistant patients
already established on standard doses of SSRIs. They found
response rates of around 50%; however this was a small
study of relatively short duration (four weeks).
The combination of mianserin and fluoxetine was examined by Ferreri et al.17 This group found significant response
rates from the addition of 60mg of mianserin to non-responders on fluoxetine 20mg.
Combinations using monoamine oxidase inhibitors and tricyclic antidepressants have also been used successfully in
treatment resistant patients. However, the dietary restrictions and the risk of a hypertensive reaction associated with
the use of monoamine oxidase inhibitors have made this
combination less popular.
Psychotherapy
The guidelines produced by NICE recommend a combination of an antidepressant and cognitive behavioural
therapy for treatment resistant depression.18 The evidence
for the effectiveness of this treatment combination is limited. One small open trial 19 demonstrated a significant
16 FORUM July 2007
reduction in depressive symptomatology in subjects, with
remission of depression achieved in 12 of the original 19
patients.
Electroconvulsive therapy and other physical treatments
Electroconvulsive therapy (ECT) is a safe and effective
treatment for depression (and is recommended by the NICE
in cases of depression that have not responded to other
mono-therapies.1) ECT is effective in up to 80% of cases of
severe or resistant depression and has a greater response
rate than either pharmacological or psychological therapies.5
There have been a number of concerns in recent years
with respect to reports of cognitive disturbance in patients
following treatment with ECT. There is often a brief period
of confusion and disorientation immediately after ECT has
been administered.
Additionally, anterograde and retrograde amnesia are
recognised sequelae following treatment with ECT. The
anterograde amnesia is mild and transient. The retrograde
amnesia that occurs is generally confined to events occurring immediately prior to ECT; however, cases of persisting
patchy memory loss have been reported in a minority of
patients.
Unilateral ECT (which selectively stimulates the non-dominant hemisphere of the brain) is associated with reduced
confusion and amnesia compared with bilateral ECT. It may
therefore be a more appropriate treatment in patients who
have experienced memory loss associated with ECT or who
have pre-existing cognitive impairment. Unilateral ECT is
however, less effective in treating depressive episodes compared with bilateral ECT and may therefore require more
applications. Approximately 50% of patients with treatment
resistant depression will relapse within the year following
ECT1; therefore, supplementary treatment with antidepressants is required.
Discussion
In summary, non-response to antidepressant medication
is a frequent problem encountered by GPs. General practitioners with experience in treating patients with depression
may wish to investigate non-response to medication in
patients and to treat patients using some of the above
approaches.
The strongest evidence for effective management of treatment-resistant depression is in the augmentation of
antidepressants with lithium and with electroconvulsive
therapy. Whilst there is evidence for the efficacy of the other
pharmacological strategies mentioned in this paper, larger
studies or meta-analyses are required to ascertain these conclusively.
There are a number of problems associated with combining medications, such as increased risks of side-effects and
adverse events as described above. Patients should be
informed of these risks prior to treatment and relevant biological parameters and investigations (blood pressure
monitoring, serum lithium levels, etc.) should be performed.
It is important that the patients’ clinical response to any
of the strategies suggested be monitored regularly.
Daniel White is special lecturer in psychiatry and Patricia
Casey is professor of psychiatry at UCD and the Mater
Hospital, Dublin
References on request