Concise Guidance for the Use of Anti-Depressant Medication in Adults Undergoing Recovery or Rehabilitation Following Acquired Brain Injury

Use of anti-depressants following ABI

The use of anti-depressants in treatment of depression following acquired brain injury is increasingly widespread. Because the volume of cases is too large and the timescale too tight to involve a psychiatrist in all cases, first line management is usually undertaken by general clinicians. However, at the current time, many people are routinely started on anti-depressant medication, often without their knowledge, and without any clear treatment plan.

Whilst there is little doubt that anti-depressant medications can be effective in improving mood for some people, they also have significant side effects, some of which can be dangerous. They are by no means appropriate or necessary in all patients.

As with any other treatment, therefore, it is important to weigh up the likely risks and benefits, to provide patients and their families with appropriate information before initiating treatment, and to have an agreed plan for assessing whether they are in fact helping, and for deciding how long to treat.

The aim of these guidelines is to provide the general physician, GP or other clinician treating patients with ABI with a safe approach to managing minor to moderate depression in the context of brain injury rehabilitation, whether in hospital or in the community, and to identify those individuals who require more specialist advice and referral to mental health services.

Guideline development

The guidelines have been developed in accordance with the principles laid down by the AGREE collaboration (Appraisal of Guidelines for Research and development) (1). A summary of the guidelines development process is given in Table 1 of the full download opposite. Details of the Guidelines Development Group (GDG) and declared conflicts of interest are given in Appendix 1. 

Background

The aetiology of depression in the context of acquired brain injury is often multi-factorial, and it is important to understand the reasons why it occurs in order to determine the circumstances in which anti-depressants may or may not help (see Box below). Anti-depressants may be helpful for depression, and possibly other mood disorders such as emotional lability, but are unlikely to be helpful where clinical features of the brain injury itself mimic depression.

• An emotional response to the sudden onset of disability and its associated life changes which may include physical, financial, vocational, and/or relationship losses.
• A direct result of the brain injury leading to altered biochemical balance within the brain and resulting change in the background level of mood
• A preceding tendency to depression (or a previously recorded episodes of depressive illness)
• Reasons why symptoms which mimic depression may occur following ABI
• Other emotional disorders associated with brain injury, such as apathy or emotional lability, may give the appearance of depression, even in the absence of a depressive disorder

Somatic symptoms which characterise depression in the normal population may occur as a result of hospitalisation or from the brain injury itself. This may lead to over-estimation of the degree of depression on standard tests. These symptoms may include:

• loss of energy, appetite and libido;
• altered sleeping habits;
• poor concentration; inability to make decisions etc.
• Abnormal physical expression of emotional status, may give the appearance of depression e.g.:
• disorders of facial expression
• flat speech patterns
• general physical slowness

Although these guidelines focus on the use of anti-depressant drugs, these are by no means the only way to manage depression following ABI, and it is important in any event to consider other contributing factors and whether they could be rectified, prior to reaching for the prescription pad.

Alternative interventions may include simple measures to address environmental or other factors which contribute to low mood (such as missing their home and family, or worries about life outside hospital.)

Non-pharmacological interventions, such as cognitive behavioural therapy or psychotherapeutic interventions, may also be suitable for patients who have the cognitive and communicative abilities to engage successfully. However it is accepted that, at the current time, these programmes are rarely available within general medical settings, and tend to be a longer-term 
intervention. For the purpose of these guidelines therefore, they are considered as a second line intervention which may follow on from specialist referral, rather than as a practical treatment alternative which is currently available to most general doctors in acute treatment settings.

The approach for these guidelines

The essential components of effective management of depression in ABI are:

• Accurate diagnosis
• Specific treatment planning and intervention
• Careful monitoring

We start from the viewpoint of a general clinician considering the prescription of anti-depressant medication, and offer a practical set of advice to support safe practice. The main practical issues for the clinician to consider are:

• Does the patient have depression which is severe enough to affect their health or to impede their recovery?
• Is it likely to respond to anti-depressant medication or are other interventions more appropriate?
• If anti-depressant medication is considered likely to be helpful, is it safe and acceptable for that particular individual?
• How to tell if it has done any good, and if so how long to continue treatment.

The evidence for use of anti-depressants in people with ABI

Epidemiology 

Although it is generally accepted that depression occurs commonly in the context of acquired brain injury and is associated with poorer outcomes(4, 5), the details of epidemiology are hard to determine. Reported frequencies for depression following stroke vary widely from less than 10% to over 50%(6, 7). Reasons for this variability include the study of different populations, at different times after stroke and the application of different measures. Longitudinal studies following stroke (8-10) have demonstrated that, at least in a proportion of cases, major depression remits between one and two years after stroke, although minor depression may persist for much longer periods. Epidemiological studies to date suggest that the frequency of depression may be broadly similar in traumatic brain injury at around 25-45%(11-14), with similar impact on psychosocial functioning(15). However, overlap between symptoms of depression and post-concussion syndrome must be properly accounted for(14, 16). Suicide rates appear to be increased by about 3-fold in people with traumatic brain injury but this may reflect pre-morbid personality as much as the brain injury itself(13)

Systematic review and assimilation of the evidence for use of anti-depressants in acquired brain injury is confounded by heterogeneity in research design, time-points of measurement and instruments used to assess depression. Most studies to date have examined short-term effects only, with no standardised assessment of adverse effects. There is little or no formal research-based evidence to date to inform the most appropriate regimen or length of treatment.

Effectiveness and safety

General conclusions which may be drawn, mainly from the literature on treatment of depression following stroke, are as follows:

• Anti-depressants have seemed reasonably acceptable to patients and are shown to bring about significantly greater reduction in depression than either placebo or no treatment. However, the treatment effect is smaller than was initially supposed. Overall, approximately four patients would need to be treated to produce one recovery from depression which would not have occurred had they been given placebo, and one patient in every ten would drop out because of side-effects(17)
• Although change in depressive symptoms is often reported, actual gains in terms of improved function or quality of life are harder to demonstrate(18). However, isolated studies have reported reduced mortality(19) and improved function(20, 21) in the treated group, compared with controls.
• SSRIs appear generally to be about as effective as tricyclics, but have fewer reported side-effects(22) and overall appear to be cost-efficient despite the slightly higher drug costs(23). They are also safer in overdose, although overdose in this situation is rare.
• Whilst there are no adequate randomised controlled studies in other forms of brain injury, a number of small open–label studies in traumatic and mixed brain injury populations(24-26) suggest that SSRIs are both effective and well-tolerated in management of depression, as well as emotional lability(27, 28). Tricyclic anti-depressants (TCAs) have possibly performed less well in this group to date, with concerns raised both with regard to treatment resistance(29) and seizure rates(30). However, the survey undertaken as part of guideline development (see Table 1)(2) demonstrates that many consultants currently use TCAs as a second- or even first-choice agent in the presence of symptoms such as neuropathic pain, hyper-salivation or insomnia, where their ‘side-effects’ may actually be desirable.

As the use of anti-depressants has become increasingly widespread so the risks of treatment have become apparent. Specific risks include:

• All anti-depressant agents lower the seizure threshold to a certain extent, and late onset seizures are a recognised problem following ABI(31-33), although the extent to which anti-depressant treatment exacerbates the risk of seizures has yet to be quantified(30, 34)

Other important risks include(18, 35):

• Interaction with warfarin, anticonvulsants and other medications which require careful adjustment of dose to maintain therapeutic levels.
• Hyponatraemia(36)
• Impotence and sexual dysfunction(37)
• Cardiac arrythmias (particularly with the tricyclic anti-depressants)
• Gastro-intestinal effects, with increased incidence of GI haemorrhage
• Diagnosis and measurement of depression

As for any condition, basic history-taking should include routine general health enquiry with open questions such as “How do you feel in yourself?”. However, for reasons discussed earlier, this may not always be sufficient to identify depression in people with acquired brain injury, and it is therefore appropriate to employ some sort of screening method as part of routine practice. More detailed assessment is then required for those in whom depression is suspected, to tease out symptoms of actual depression or lowered mood from the general effects of ABI, and to quantify the severity of mood disturbance prior to considering treatment.

Screening methods for depression

Some authors have proposed that the simple ‘Yale question’ (“Do you often feel sad or depressed?”) provides as good a screening assessment of depression as any(38). The advantages of this single question its simplicity and timeliness. However, a dichotomous answer of ‘Yes’ or ‘No’ may in itself be problematic.

Firstly, it requires intact comprehension and at least a reliable ‘yes/no’ response which may not be present in some patients following brain injury.

Secondly, the question is not so simple as it may first appear - in fact it contains two different components, to which the response may be different. For example, it is not uncommon for patients to feel sad about their loss, but not depressed. There also needs to be some comparison with their normal mood state.

As with all screening tests, a dichotomous response does not provide a sensitive measure against which to assess the benefits of treatment, particularly in cases when there may have been some partial improvement in mood.

Quantification of depression

A number of depression scales have been developed to quantify depression in a more graded manner. These exist in several different formats which may be chosen to suit the patient’s capabilities in response:

• Questionnaire-based tools – may be completed at interview or by self–report where the individual has sufficient verbal skills.
• Non-verbal rating scales – such as visual analogue scales in different forms, may be useful where verbal communication is limited, although facilitation will often be required.
• Scales based on observation of behaviour, such as crying, withdrawal, apathy may be useful where the individual is unable to respond to either of the above.

Examples of these various types of instrument are detailed further in Appendix 2. Some of the scales require special training and experience to administer, others are more intuitive. They may be useful in determining the extent of low mood and in monitoring response to intervention. However, they should not be used as the sole indication for initiation of treatment. There is no one tool which may be applied universally, but it is appropriate for teams to familiarise themselves with a chosen selection, so that they reach a shared understanding of the meaning of a particular score. Further more detailed assessment may then be undertaken through interview and/or observation. Figure 1 presents a proposed schema for screening and assessment of depression at different levels, and the extent of clinical expertise which may be required.

Continued monitoring

Screening and assessment of depression carries no benefit if it is not followed through to appropriate treatment planning and continued monitoring to ensure response. Whatever the assessment process used, it must be timely and practical to allow for repeat on subsequent occasions for comparison.

Capacity and consent

Many people believe that depression carries a certain stigma. Patients sometimes report that they feel pressurised into taking anti-depressant medication when they do not believe they are depressed, or when they would rather use other methods to combat the symptoms. It is important to ensure that they give their informed consent to treatment, if they have the capacity to do so.

The capacity to consent to treatment requires the patient to be able to a) understand and retain information about the treatment proposed and any alternative options that may be available and b) weigh up the benefits and risks associated with treatment, including any possible consequences of declining treatment.

People who have acquired brain injury sometimes have cognitive and communicative difficulties which limit their capacity to make informed decisions about their treatment and to give consent. Alternatively, they may be able to understand, but their judgement can be clouded by the depression itself – especially where hopelessness is a prominent feature. In these situations assessment may be complex:

The treating physician is required under common law to provide management in the best interests of the patient who lacks capacity, but those ‘best interests’ must be carefully established.

Doctors have a duty of care to make every effort to ascertain the patient’s wishes with regard to each individual intervention and, where this cannot be determined, to discover what their attitude to treatment might have been, but for the brain injury.

Family and relatives can play an important role in indicating the likely wishes of the individual in the light of their pre-morbid values and beliefs, but cannot give consent for them.

A clinical neuropsychologist and/or a speech and language therapist may be helpful in assessing the individual’s cognitive abilities or in enhancing communication to ascertain their level of capacity for consent and their wishes with regard to treatment.

In complex situations where the patient lacks, or may lack, capacity and treatment is considered which appears to be against their wishes, it is appropriate to seek the advice of a psychiatrist both with regard to determining capacity and any possible application of the Mental Health Act?

Even when patients can give consent, they may feel uncertain about why treatment is being recommended. Every effort should be made to provide information in a variety of forms and at different times, including leaflets to take away and details of who to contact for further information. A sample information sheet is given in Appendix 3.

Family members are often involved on a practical level in encouraging or reminding patients to take their medication. It is generally good practice, therefore, to involve the family in decisions regarding treatment, and to have their consensus wherever possible, since this may help to avoid any potential later conflicts. However, if the patient has capacity, their agreement must be sought before approaching the family.

Choice of an anti-depressant

In the absence of formal research to inform the choice of anti-depressant agent, the following is adapted from Royal College of Physicians’ Guide: The Psychological Care of Medical Patients(39).

If anti-depressant therapy is considered appropriate, and if the individual agrees, to treatment, the choice of drug should be matched to the patient’s individual needs as far as possible(40) depending on the effect and tolerability of treatment, whether sedation is required and the risks of interactions(41)

Selective serotonin re-uptake inhibitors (SSRIs) have generally replaced tricyclics as the drugs of first choice in depression because of their better side-effect profile, which may be particular important in people with ABI who tolerate side-effects such as sedation poorly

Six SSRIs are currently available - fluoxetine, fluvoxamine, paroxetine, sertraline and citalopram and escitalopram. There are important pharmaco-kinetic differences between them(41) notably in their ability to inhibit hepatic cytochrome P450 iso-enzymes which are responsible for the metabolism of many drugs. In vitro studies suggest that citalopram and sertraline are least likely to inhibit these iso-enzymes and therefore least likely to cause interactions with other drugs. A recent survey of rehabilitation consultants and geriatricians in the UK(2) has demonstrated these two agents to be the most common first choice for management of depression following ABI at the current time.

Escitalopram is a newer agent, which appears also to be highly selective with minimal inhibition of cytochrome P450 iso-enzymes. Trials suggest that it is at least as effective as citalopram in the management of severe depression(42, 43) but it has yet to be evaluated in the context of stroke or other forms of ABI.

Other more recently introduced anti-depressants include nefazodone, venlafaxine, mirtazapine and reboxetine These have significantly different pharmacological properties and are claimed to have greater specificity, equivalent or better efficacy and fewer side-effects than the earlier classes of anti-depressants(44). As yet, however, they have not been fully tested in the context of ABI, and they are also significantly more expensive. At present they should be used as second line drugs, when SSRIs have not been effective, or have produced unwanted side-effects or drug interactions.

In the absence of specific evidence on which to base firm advice, a pragmatic approach would be as follows:

• The clinician should familiarise themselves with one or two agents in each class
• A specific SSRI, such as citalopram or sertraline, represents a reasonable first choice agent (13, 18, 45) unless the anti-cholinergic effects of a tricyclic agent are positively desirable (for example sedation or suppression of hyper-salivation).
• The patient should be kept under direct clinical monitoring whilst the drug is built up to an effective dose to ensure that it is tolerated and producing the required improvement in mood.
• If not tolerated or effective, it is appropriate to withdraw the medication and change to a drug from a different class, after an appropriate washout period depending on the agent used (with appropriate advice from the pharmacy).
• In the absence of response to or tolerance of a second agent, anti-depressant drugs are unlikely to provide the solution and should usually be discontinued.
• Depression in the context of ABI is usually transitory, and so in the majority of cases treatment can successfully be withdrawn after 4-6 months. At the end of this time, there should be a planned graded withdrawal of the medication, and the patient should be warned to expect rebound symptoms.
• A minority of patients may experience relapse over time, and require longer-term treatment. In this case it is appropriate to seek formal psychiatric advice.

The details of approach will depend to a certain extent on the individual and the context of treatment.

Age: There is no reason per se, to consider that older adults are different to younger adults, when defining treatment recommendations. However, there may be some age-associated characteristics which affect the approach to intervention – notably co-morbidity and poly-pharmacy - which may render them susceptible to side-effects and affect the choice of anti-depressant used.

Rehabilitation setting: The context of rehabilitation and the time-scale over which intervention is offered may affect the approach to management, particularly with regard to arrangements for review and follow-up. In-patient programmes are usually offered on a fairly short time scale, with pressure for prompt intervention in order to maximise participation in the rehabilitation programme. In community rehabilitation settings, patients are often followed for longer, which may give more opportunity for watchful waiting and to observe the effects of treatment. Either way, careful consideration must always be given to follow-up when the patient moves from one setting to another, to ensure that treatment is properly monitored and is withdrawn at the appropriate time.

Implications for Implementation

Implementation of these guidelines will involve investment to provide:

• Improved training in assessment and management of depression for all clinicians working with ABI patients.
• Better information and awareness among the general public with regard to depression and its management in this context.
• Better monitoring, follow-up and communication between clinicians across the different settings.

However, successful implementation of the guidelines will be expected to reduce unnecessary, unwanted, and potentially dangerous use of medication in a vulnerable patient group – with overall cost-effective results.

Screening

The possibility of depression should be considered for any patient with acquired brain injury.

At the very least the patient should be asked “Do you often feel sad or depressed?” at each assessment.

For individuals who are unable to respond, staff should consider whether their behaviour suggests depression (e.g. apathy, withdrawal, non-compliance, excessive crying etc.)

Assessment should include inquiry for prior psychiatric history or any previous use of anti-depressant medication, and should take into account previous personality and emotional traits, and change from normal personality

The cause of apparent distress should be explored with the patient by an appropriate professional

More detailed assessment of mood

For patients in whom depression is suspected, more detailed assessment of mood should be undertaken:

• using validated instruments, interview and/or observation
• to determine the severity of depression and contributing factors C

Before considering treatment for depression:

The clinician should consider the following questions:

• Is depression interfering with their quality of life or progress in rehabilitation?
• Is anti-depressant treatment really needed at this time or are other interventions more appropriate in the first instance: For example are there simple interventions which would improve quality of life and hence boost their mood?
• Has a period of watchful waiting (i.e. at least 2-3 weeks) demonstrated that the problem is not resolving spontaneously?
• Has the patient and their family (where appropriate) been properly informed about the nature of depression and different treatment options?

Before starting an anti-depressant, the clinician should consider the following questions:

• Are there any contra-indications to treatment?
• Do the likely benefits outweigh the risks?
• Has the patient given informed consent – or if unable to consent have appropriate procedures been followed?
• How will you know if it has worked? 

Formulating the treatment plan

Anti-depressants should be prescribed according to an agreed treatment plan which includes:

1. Baseline assessment using an appropriate validated measure of depression
2. Baseline urinalysis, and blood samples for FBC, U&E and LFTs
3. Selection of an appropriate agent
4. Clinical review of initial response to optimise dose
5. Repeat assessment of mood after 6-8 weeks, (using the same measure as in 1.) to assess the effect 
6. In the case of a positive treatment response, an agreed treatment plan outlining:
   1. length of treatment (usually 6 months)
   2. procedure for withdrawal at the end of treatment and who will supervise this
7. If the response to an appropriate dose of medication is poor or absent at 6-8 weeks, the drug should be withdrawn and alternative treatment or referral considered C

During treatment

Patients should see their doctor regularly during treatment and any clinical deterioration during treatment should be investigated. In particular, the following should be considered as possible side-effects of treatment:

Hyponatraemia, seizures, GI Bleeding, anti-cholinergic symptoms, sexual dysfunction, sedation, hallucinations, increased confusion, headache C

Referral for formal psychiatric review

The patient should be referred for formal psychiatric review if:

• Depression is very severe or resistant to treatment
• There is a past history of psychiatric disorder
• If the patients shows evidence of suicidal ideation or intent – this should trigger emergency referral
• If it seems likely that the patient needs to be treated under section of the Mental Heath Act or equivalent C

Withdrawal from treatment

At the end of the treatment period (4 to 6 months) there should be a planned withdrawal of anti-depressant medication, which should be undertaken gradually over a period of 1 to 2 months.

Prior to withdrawal:

• Their mood should be re-evaluated using the same measure as at baseline
• The patient / family should be warned to expect rebound symptoms
• In the event of significant longer lasting relapse of depression, the need for long-term treatment should be considered and formal psychiatric advice sought. C

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Extra Resources:-

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Concise Guidance
ABI - Appendix 1
ABI - Appendix 2a
ABI - Appendix 2b
ABI - Appendix 3
ABI - Appendix 4

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ABI - Additional Data
ABI - Additional Data