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Treatments for Depression: A Q&A with Andrew McIntosh

As part of Depression Detectives, we’re holding weekly Q&As with scientists and experts who work on depression or related topics. Our Q&A last week was with Andrew McIntosh, a psychiatrist from the University of Edinburgh.

Hi Andrew!

Andrew: Hello everyone. My name is Andrew McIntosh. I’m a professor of psychiatry from the University of Edinburgh and an NHS Psychiatrist in the Royal Edinburgh Hospital. I’m happy to answer any questions you have about treatments for depression. I’ll be here from 9pm until 10pm


Depression Detectives member E (DD E): I would like to ask you about the long term effects of psychotropic medication (lithium and amitriptyline), by which I mean 3 decades or more?

DD A: My question is similar to E’s. What does current research say about patients using an SSRI like Sertraline long term? >3 years.

Andrew: Not very much. The side effects of SSRIs are thought to be greatest at the very start of treatment and with every increase in dose. You tend to break them down more effectively over time, as your liver tries to eliminate them.

As you age however, other illnesses may develop that impact how you deal with the SSRIs. These illnesses (e.g. of the kidney) can mean that the blood levels of SSRIs rise over time and you might get worse side effects whilst remaining on the same dose.

There are long term side effects from lithium with continued use. There are 2 in particular – hypothyroidism and diabetes insipidus. 

Hypothyroidism, a common condition is where the thyroid doesn’t produce enough thyroxine. It can be treated by giving thyroxine in a tablet every day. Not ideal, but that’s what many people choose to do. Diabetes insipidus is a condition where the kidneys find it progressively difficult to concentrate your urine. It can be quite disabling and can lead to people drinking and urinating many many times a day. It can’t currently be reversed.

DD M: that’s a bit of a bugger considering I’ve been taking SSRIs (and a few years of SNRI in the middle) for over 20 yrs 😬

DD A: So does that mean you will eventually need higher and higher doses to get the same effect?

Andrew: That could be the case. However (and sorry to complicate this) but the levels of SSRI in your blood aren’t a very good indicator of your response. So the link between dose over time and your response to the treatment isn’t very clear and differs between people

DD M: That’s really interesting.

Andrew: I think so too. If it were as simple as a lack of serotonin, it should be more straightforward. In practice, research suggests that its your brain adaptation to the SSRI that leads to the treatment response. So its fascinating, but there’s still much we don’t know

DD C: Would you be able to explain a bit more what it means that your brain adapts to the SSRIs?

Andrew: I’ve just see your comment. It’s really interesting- after a week or two of treatment, your serotonin returns to normal, and your depression starts to get better. We don’t understand why- but isn’t it fascinating?

There have been some reports of other types of issue arising with long term treatment, such as abnormal movements. These don’t seem to be very common and they are more controversial

DD M: Is there likely to be any permanent changes to neurobiology with long term use at all?

Andrew: Probably not – on 2 counts

  1. We would like treatment with long term antidepressants to eliminate the need for treatment years later, by altering the neurobiology. Unfortunately I don’t think that’s what we really see. We DO see treatment effects continuing with sustained treatment over 2 years however.
  2. We don’t see convincing changes in long term brain structure or function many many years out from treatment. There are some studies that have shown this, but its not convincing yet in my opinion.

Note from Andrew: As I look through my comments, I’m reflecting on the response I gave saying that there were no convincing long term changes in the brain with antidepressants. While that may be true, it’s more difficult to study than you’d think and there’s still work to be done there.


DD E: I am interested in things people do to ease their depressive symptoms – how much evidence is there that they help, and how much can they help relative to (or even in addition to) antidepressants? Things people might choose to do themselves without medical input like smoking marijuana or regular exercise or cutting off unhelpful relationships.

DD M: Well, there’s eating excessively or drinking alcohol too?

DD E: Maybe another way of phrasing it is “how effective can behaviour change be versus antidepressants?

Andrew: Lots of good evidence for this… CBT – people often attend to the ‘C’ – cognition/thought aspect. Changing ways of behaving was one of the core components of CBT – the ‘B’ if you like.


DD S: Based on discussions on the group, when a person first goes to their GP with depression, it seems they are likely to be prescribed antidepressants, and perhaps some short term CBT. Is that because these are the best treatments? Or are they what is most available?

Are there other treatment options?

Andrew: There are lots of treatment options, but these are some of the ones for which we have really good evidence. The advantages of antidepressants are you can start right away. There are advantages for CBT too (such as its effective, and you don’t need to take a medication at all potentially)- but you can rarely start straight away.

DD S: Thanks Andrew. Some people in discussions had felt they would have benefitted from longer term CBT, or from other talking therapies. Are those difficult to come by because they are expensive, and GPs don’t have the funding? Or is it because the HCP genuinely believes they won’t help?

What are the constraints on doctors when prescribing treatments?

DD M: Do you think IAPT is helpful as part of the treatment options?

DD I: For others IAPT = The Improving Access to Psychological Therapies (IAPT) programme (talking therapies) which began in England in 2008 –

Andrew: I think there aren’t enough clinical psychologists to meet the number of people who could want therapies and waiting lists are significant. IAPT was an NHS England initiative that helped to expand psychological treatments in England. It didn’t make it north of the border. There aren’t any constraints on doctors prescribing treatments, but someone has to be available to provide them.

Doctors usually refer to clinical psychology – who do an assessment and decide on the best talking treatment. I don’t generally refer for CBT, although I know that CBT and/or mindfulness based therapies are the more likely treatments that people will recieve. They both have solid evidence for their efficacy and lots of people find them helpful

DD S: I would say availability of providers is a constraint then:-).

Is that another advantage of CBT then? It doesn’t take a qualified clinical psychiatrist to do it, and it can be given by a nurse with some extra training.

Andrew: It can also be delivered by computer.

DD M: Do you think it is different in England, and in Wales in practice? And also for large cities e.g. London? I live in Greater London.

Andrew: I’m not sure, sorry. I think accessing psychological treatments is perhaps easier in England. I don’t know very much about Wales. I know lots of psychiatrists and psychologists in E&W and they seem to be facing similar challenges


DD N: Hi Andrew, thanks for joining us. I’d be really interested to know about the different types of antidepressants – what are the main similarities/differences and what’s the best way to find the right option?

Andrew: Different antidepressants work by affecting 2 main chemicals (serotonin and/or noradrenaline) in the brain, but in fairly subtly different ways

Some cause the brain to stop recycling them in the brain cells (e.g. SSRIs), some do this for both chemicals (tricyclic antidepressants like amitriptyline) others working in complimentary ways …. but they are more similar that they are different in a way

The *real* difference between them is in their side effects. Some medications are slightly more effective than others (e.g. amitriptyline) – but come with worse side effects. The side effects differ a lot, but their efficacy differs by less.

It’s mostly a matter of choosing your side effects initially (when I see people in clinic). For the first episode, docs generally treat with SSRIs as these are generally effective and have some of the best side effect profiles

DD T: Thanks Andrew McIntosh What is happening with these 2 main chemicals when someone has depression? You mentioned they are recycled in brain cells, can you talk about why that happens and what we know about how that changes with depression?

Andrew: The brain is designed to send signals using these chemicals from one nerve cell to another. When a message arrives at the end of one brain cell, it may be passed onto the next one using a chemical signal.

Once the chemical has done its job, the nerve cells then hover it up again, so that it can be sent again when it’s needed

Disclaimer: this is the gist, but an oversimplification


DD L: Hi Andrew, do you think antidepressants are over-prescribed?

Andrew: That’s a tricky question! I would guess that there must be some people who are receiving an antidepressant when another treatment would suit them better. However, I do not think that they are generally overprescribed.

I think the idea that antidepressants are overprescribed has been created by 2-3 things:

  1. When SSRIs came on the market, you could achieve the recommended dose (the defined daily dose, or DDD) immediately. Whereas earlier drugs had more side effects and people often didn’t get to the usual effective dose. This led to an apparent spike in antidepressant prescriptions
  2. The recognition of depression in GP when I was training was understood to be grossly inadequate/under-recognised. Over the last 20 years GPs have been better at spotting depression, and of course that has led to more prescriptions.
  3. In my opinion – when someone is treated for migraine, cancer, MS etc — people rarely question whether this is appropriate or not. When antidepressants are mentioned, it’s often in the context of ‘mind altering drugs’ or ‘masking the underlying issues’. I personally believe that this is a kind of shaming/stigmatisation of people taking antidepressants that you don’t see elsewhere.

DD S: That’s really interesting. Would you say then that there was a lot of under-diagnosed depression which was sending people repeatedly to the doctors with other things? (Or, indeed, that people were just miserable a lot, without even going to the doctors…)

Andrew: There’s a lot of undiagnosed depression out there. We know that, because we’ve done studies of the general population, and we see people with depression who have never been to their GP or a psychologist or counsellor

One of the first people I treated for depression had MS. They hadn’t been given treatment I believe because sometimes people see the symptoms as understandable. I think there are a lot of people with cancer who don’t receive treatment that could help them

DD M: I was talking to a friend who worked in the pharmacy industry years ago who thought they were pushed rather forcefully by reps.

I’m guessing also that some GPs prescribed inappropriately at that point?

Andrew: I think that’s true…it’s very different now (for the better)


DD A: How do you differentiate between depression, depression from stress, depression in the context of autism, and negative symptoms of schizophrenia? Sorry, probably a weird question.

Andrew: Not weird at all. In each case, depression has to meet the same general criteria. Sometimes, it can be difficult to tell whether someone is depressed in each of these situations however as some of the features of depression overlap with that of the other condition (eg schizophrenia and lack of motivation, autism and social withdrawal). However, I think it is usually possible to tell because of the *change* in mood and behaviour in a person. It really helps to have a friend/relative there, or someone who knows the person very well.

DD A: That does make good sense, but seems not so defining. For instance, I typically have social withdrawal when depressed and lack of motivation generally. I wonder in the context of my daughters, who have been diagnosed with autistic spectrum disorder and learning disorder (learning disorder for me as well, but forgotten until I was in my thirties). In part, it is why I supported the finding a diagnosis for them, as I did not feel the treatment I received was helpful, though people meant mostly well. I will be briefly honest and say that some were not so helpful.


DD N: If money/resource/capacity were not a factor (or we lived in an ideal world with a fully funded NHS for mental health treatments) what would treatment look like? Would there be more time taken to diagnose causes of depression meaning more bespoke treatment options, for example?

Andrew: Great question! I think many issues would be the same and antidepressants would be used a lot. However, I think there would be a more rapid access route to refer people to trained therapists (e.g. nurses, other caring professionals) for straight from the GP than coming to hospital.

I’d like to think that we would also have what I’d call a learning health service.

That’s where information on your treatment is continually fed back for research and other purposes routinely so that we continue to learn what treatments work best for each individual, and we are in a cycle of continuous improvement.

DD N: yes – that makes a lot of sense! Would help the individual and the wider thoughts on best treatment practice.

DD A: massage. every. day. and trees everywhere! And government pays musicians!


DD E: Also, I have heard it said that antidepressants are like a sticking plaster over a gaping wound. It might hold you together but can never heal the underlying problems. Is that fair to say? Or part of stigmatising narrative?

Andrew:  I can see that in the case of a particular individual, this narrative might make some sense. I can see people in abusive or unhappy marriages, and while they *are* helped by the antidepressant, I’m not persuaded that’s all they need to do

In some cases I think that people in very difficult circumstances can be helped to find the motivation to change their situation through antidepressant treatment.

There’s a theory of depression called learned helplessness

It’s based on human and animal research, but it states that depression happens when you no longer believe you have the agency to change your current circumstances.

You can test this model in humans and (and I’m sorry if this offends) in animals (usually rats). It turns out that there is some evidence from the animal studies that antidepressants tend to ameliorate learned helplessness

So – long answer. In summary, its complicated and its difficult to know. I don’t conclude that antidepressants are a sticking plaster however. They can be highly effective and help people help themselves out of some very intractable problems


DD A: Has there been any recent research on EMDR as a treatment for depression or anxiety?

Andrew: EMDR has been studied for Post Traumatic Stress Disorder, but has received relatively little attention as a treatment for depression as far as I know.

I did a very quick pubmed search here, and you can see there are people actively thinking about this:

DD A: thank you! I’ll check it out.


DD C: What is the evidence for/against the view that antidepressants might be depressogenic (causing depression) over the long term?

Andrew: I don’t think there’s any good evidence to suggest that is the case.


DD E: Having just watched the leaders debate only one, William Rennie made any reference to funding mental health. Do you have a viewpoint on mental health funding and how it could be increased. I would happily pay a bit more in tax if I was assured it went to mental health.

Andrew: I’ve just watched some of it too! I think if funding was tied to the suffering and years lived with disability in a rational way, mental health would receive more funding. I think we all need to make the case repeatedly – and write to our MP/MSPs. I wrote to Christine Jardine recently on a matter relating to mental health (she’s my local MP, this isn’t an endorsement btw!). She was surprisingly responsive and it’s worth doing if politicians think they will lose votes by not supporting mental health.


DD A: I was wondering a bit about personalized medicine. I have a sister with a CYP and serotonin transporter variant that makes her very sensitive to some SSRIs who was subsequently diagnosed with bipolar II. Do you think that guidelines to check for these types of differences will become (or should become) incorporated into guidelines? Though I know that some see it as possibly unmasking bipolar disorder, to me it seems more like feeding someone with prediabetes doughnuts.

Andrew: Interesting question – let me answer the first part

I do think that routine genetic testing will come one day. I think it is already justifiable in learning disability diagnosis and will become useful in a number of conditions soon.

I think that it will also be helpful for depression treatment targeting too. Highlighting people more likely to have a good response, as well as people likely to have side effects.

The evidence for these tests isn’t quite there yet (although there are some disreputable companies who are already offering testing)

This is an area of research we’re investigating

My hope is that genetic testing research for depression and depression treatment will be brought along and developed further as this becomes more commonplace for other conditions. I think genetics will be part of a learning health system eventually

DD A: My sister was encouraged to be tested by her psychiatrist, because of a history of developmental disorders (though not exactly descriptive, since vs IQ tends to be very high in my family, though generations, and verbal IQ catches up to normal or above). And the commentary on her genetic variations came from a phd in neuroscience (friend of mine) who said a person with these variations should never be given an SSRI. For context, they felt that my quick response to SSRI might indicate that I was a good candidate, and they had taken SSRIs in the past, so they were not anti-medication.


DD N: That’s all we’ve got time for! Thanks so much again for coming and answering so many questions Andrew.

Andrew: Thanks for inviting me along today. I hope you’re finding all of the discussions interesting and I’m looking forward to hearing more about your experience of this group some time


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