Need to know - prescribing antidepressants
Beginning our depression special report, Professor Linda Gask answers questions from GP Dr Linden Ruckert
Beginning our depression special report, Professor Linda Gask answers questions from GP Dr Linden Ruckert
1. What is your preferred first choice antidepressant?
My first choice would be an SSRI – as recommended by NICE1 – and I would usually go for citalopram. It's not a potent inhibitor of most cytochrome enzymes so it's pretty good in terms of potential interactions. I know fluoxetine is also popular and cheap but in my experience it's also more likely to cause agitation.
2. How good is the evidence around the value of specific antidepressants? Most of the trial work has been done on inpatients and often of surprising short duration.
Severity of depression is crucial here, not setting of treatment. The evidence for antidepressants in milder depression is very poor – hence the moves in QOF to inform treatment by measuring the severity of depression.
Patients in hospital settings do have depression at the very severe end of the spectrum and there is also considerable criticism in the literature about the quality of the evidence for antidepressant treatment.
The most severely depressed patients tend not to be included in trials despite being more likely to show a true drug effect, and the placebo effect is greater in mild depression. The evidence for antidepressants in moderate to severe depression is there (see NICE guidance), but you do need to assess severity.
3. It is often said that a higher dose of tricyclics must be used to be effective – which many patients wouldn't be able to take and stay upright – but experience tells us patients do respond to lower doses. What is your view?
The jury is still out on the low versus high dose of antidepressants debate – there have been too few well-conducted studies. Tricyclics are also very good sedatives and the placebo effect is greater in milder depression, as I've already indicated. Of course, like everyone else I have seen effects at low doses.
However, tricyclics have other problems too. Tricyclics other than lofepramine should be the last choice now, and Dosulepin (dothiepin) should only be used after consultation with specialist care.
4. Some drugs have a licence for anxiety specifically but I am not sure if that means they work better or just that they have a licence, for example paroxetine?
Frankly, it is because they have applied for the licence. As far as we are aware, this is a drug class effect. A useful review of this area was published by the British Association for Psychopharmacology two years ago2.
5. Clomipramine does seem to work in OCD but why should that be?
Because the drug shares the pharmacological properties of the tricyclic group of antidepressants from which it is derived, but can be distinguished from other tricyclics by its potent effects at inhibiting the synaptic reuptake of the neurotransmitter serotonin.
However, its effects are not selectively mediated by serotonin mechanisms. As a tricyclic, clomipramine is associated with the adverse effects and toxicity in overdose that typifies this group of drugs. For this reason it is usually considered second-line after SSRIs for patients whose symptoms have failed to respond to SSRIs or who are unable to tolerate them.
6. Some patients swear sertraline is best for OCD but can we explain that scientifically?
The SSRIs are all probably equally useful. But some people will experience side-effects and tolerability problems that others will not. Of the SSRIs, sertraline has the most affinity for the dopamine transporter so theoretically it could be a dopaminergic effect at high doses. But this has not been shown in practice in the dose range used in humans. There is some evidence for the efficacy of antipsychotic augmentation of SSRIs in OCD.
7. Who should receive MAOIs and the newer related drugs? Someone suggested they have particular use in social phobia.
The old MAOIs are really only used now in resistant depression in a small number of patients by psychiatrists, and then not as much as they were in the past.
The first choice in drug treatment for social phobia, if that is the choice, is an SSRI. The problem is that treatment does have to be continued for at least a year and probably longer. In my experience, people notice a considerable improvement in their social abilities and don't want to come off medication.
Moclobemide is a second-line drug for social phobia and an alternative second-line treatment in depression after an SSRI. Washout periods are required when changing to and from moclobemide.
8. What regime do you use for stopping antidepressants? Should the speed of withdrawal be determined by the length of time on the drug?
Generally, antidepressants should be discontinued gradually over a four-week period but this is not required with fluoxetine which has a long half-life. The shorter the half-life of the drug, the more important this is, for example with venlafaxine.
Discontinuation is difficult for some people especially those who:
• don't take the medication regularly
• develop anxiety symptoms at the start of therapy
• are on other centrally acting medication
• have had withdrawal reactions before.
The longer the patient has been on them, the slower withdrawal should probably be.
A characteristic SSRI discontinuation syndrome appears to exist. It is usually mild, commences within one week of stopping treatment, resolves spontaneously within three weeks, and consists of diverse physical and psychological symptoms, the commonest being dizziness, nausea, lethargy and headache.
SSRI reinstatement leads to resolution within 48 hours4. However, this can be confused with the return of anxiety if symptoms appear to be delayed.
9. We all have patients who get to a certain dose and don't seem to be able to stop – and then wish to continue on a sub-therapeutic dose and feel this prevents relapse – is that reasonable?
It's one of those situations where you need to negotiate. If the person has had two or more episodes of depression in the previous two years then it would be reasonable for them to stay on medication. I do get concerned when doctors try to ‘wean a patient off' medication when they would clearly benefit from staying on it for treatment of a relapsing, life-threatening disorder associated with persistent life stresses that cannot easily be managed any other way.
There is, however, no good evidence that lower-than-standard doses are effective in maintenance, except in the elderly.
10. Some psychiatrists say those who have had more than two or three significant episodes of depression should stay on antidepressants for life. What is your view?
I certainly think this is an indication to consider longer-term treatment. But again it is a matter of choice and negotiation. Some people can use psychological therapy to make the kind of changes to their life that will ultimately enable them to manage without antidepressant medication. Other people cannot. They need medication to continue to be able to function effectively in the face of stresses they cannot change.
I would never advocate anything ‘for life'. All people's lives change eventually, and they should always be made aware of other options.
11. Do you use tricyclics much anymore and if so for whom?
The only tricyclic I would use now is lofepramine because it is less cardiotoxic.
Tricyclics are useful when:
• you know they have worked in the past
• you really want a sedative effect
• a person cannot tolerate SSRIs
• you have tried other options and they have failed.
There is also some evidence that they are more effective than SSRIs in the more severe forms of depression.
12. How valuable are the NA uptake inhibitors like venlafaxine, and mirtazapine? NICE seems to have relaxed its line a bit so should GPs be initiating these? Who do they really work for?
Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) and NICE considers it to be a second-line antidepressant for use after an SSRI. The problems are that it is very sedative – although this can be an advantage – and it causes weight gain. It can also be used in combination with an SSRI such as citalopram in resistant depression but this is really a third-line treatment.
Venlafaxine and duloxetine are slightly different. They are both serotonin and noradrenaline reuptake inhibitors (SNRIs), third-line treatments, and there is some evidence for them being more effective in more severe depression. However, 75mg venlafaxine is really acting only as an SSRI and at least 150mg is needed for the dual action effect – an issue which may have cost considerations.
GPs can initiate this up to 300mg a day but they should check blood pressure on initiation of the drug, and consider obtaining a baseline ECG if there is any concern about cardiac dysfunction.
13. Swapping antidepressants is a fraught area. The Maudsley handbook often recommends ‘careful cross tapering' or a gradual withdrawal, wash out then starting another one. What do you recommend?
The Maudsley handbook5 is the best detailed guidance there is and I use it regularly as it is impossible to commit all its advice to memory. But Stephen Bazire's book, Psychtropic Drug Directory6, is very useful too. Some psychiatrists may be more ‘gung-ho' than GPs – familiarity may breed complacency – but I really wouldn't advise that approach.
14. How useful are questionnaires such as PHQ 9 in deciding who to start on antidepressants?
Really quite good. The PHQ-9 has now been validated in a UK sample and within my team we use it regularly to help inform decision-making about the need for antidepressants.
If the PHQ-9 is consistently over 20 then an effort should be made to persuade the patient to accept an antidepressant. If it is between 14-20 you really have a choice between psychological treatment – including guided self-help – and antidepressants. Below 12-14 I would not consider this unless the patient has a history of more severe depression.
The PHQ is also good at telling you about change over time and whether treatment is actually doing anything.
15. Would you say the ‘six months after improvement' rule should apply to all depressed patients starting antidepressants? Would milder cases need less and those with worse/previous episodes need more?
My response would be to ask whether antidepressants are indicated at all if the depression is ‘mild'. I think we have to be properly selective about who we put on antidepressants, but then, when they are on them, ensure they stay on them for the proper length of time. I suspect quite a few people who only take them for a couple of months would have improved without them.
15. How do you manage those without a diagnosis of bipolar disorder who seem to become a bit ‘high' after starting antidepressants?
You keep a close eye on them, to ensure that they do not get any higher, and if clear symptoms of hypomania emerge refer them to specialist care and taper down the antidepressants.
There is undoubtedly a broader spectrum of ‘bipolar' illness than we once thought. Some people have episodes of hypomania as well as depression (type II) but do not progress to mania (type I). There are others who only experience cycling of mood induced by antidepressants.
We need a lot more research on these mood disorders in British primary care settings, as most of the work has been done outside the UK .
16. Which is the current favoured mood stabiliser and do they have a place outside of bipolar disorder?
Lithium is still used, but valproate and lamotrigine are also used extensively, sometimes in combination. These should never be commenced in primary care. Mood stabilisers are also used in specialist treatment of resistant depression.
17. What is the current consensus on the risk of suicide and antidepressants?
The consensus is that they do not increase the risk of suicide in adults but there is a greater risk in adolescents. Fluoxetine is the only antidepressant licensed for under-18s. There is no doubt that the SSRIs can contribute to agitation and careful monitoring of symptoms, side-effects and suicide risk – particularly in those aged under 30 – should be routinely undertaken.
Professor Linda Gask is professor of primary care psychiatry, University of Manchester, and hon consultant psychiatrist, Salford PCT (primary care mental health team)
I have received money from a number of different companies for lecturing on the topic of treatment of depression and also research support in the past five years from Servier for a study on patients views about antidepressant medicationTake home points What I will do now What I will do now
Dr Linden Ruckert reflects on the answers to her questions
• I will continue to use citalopram first-line as an SSRI unless there is a clear reason to use another drug. I am pleased to hear the therapeutic action on anxiety is a class effect.
• How much is placebo effect I am not sure, but some patients definitely believe a smaller dose of tricyclics helps and I am pleased to hear there is some debate about effectiveness.
• Experience suggests to me those on longer-term SSRIs need to discontinue them over a longer time but knowing that 48hr of resuming the drug will stop discontinuation symptoms.
• It is helpful that we can now start venlafaxine in general practice but useful to be reminded of the need to check BP and possibly an ECG.
• I am glad to hear all those PHQ9s I have completed are of proven value and accuracy.
• I will reassure adult patients that there is now increased risk of suicide due to SSRIs themselves.
Dr Linden Ruckert is a GP in north London