Depression: Choosing pharmacologic treatments

Zainab Samaan, Roman Jaeschke

Dr Zainab Samaan, associate professor in the Department of Psychiatry and Behavioral Neurosciences at McMaster University, joins Dr Roman Jaeschke in a discussion about pharmacologic treatment of depression.

Roman Jaeschke, MD, MSc: Good afternoon. Welcome to another episode of McMaster Perspective. We were talking in general terms about depression, and now we are going to talk a bit more about pharmacotherapy and psychotherapy.

We were discussing the fact that the number needed to treat (NNT) with antidepressants to achieve additional remission within a relatively short period of time is actually not too bad. At first we thought that it could be better, because it’s anywhere from 5 to 10, depending on where you look, but in reality, when we reflect on the fact that antihypertensive or antilipid/anticholesterol treatment would have an NNT of anywhere from 40 to 60 to 100 over a period of years, antidepressants are not that bad.

My question is, when there is such an array of different antidepressants these days—different classes, different letter abbreviations—what determines how a given antidepressant is chosen?

Zainab Samaan, MSc, PhD: It’s a really good question. Thank you, Dr Jaeschke. We are very fortunate in our time to have the choices. Many years ago there were only the old-generation tricyclic antidepressants that caused a lot of problems when it comes to side effects and toxicity.

The choices are determined by many factors. If you look at the clinical guidelines, the recommendation is to start with the most straightforward, the mildest type of medication, which is usually the selective serotonin reuptake inhibitors (SSRIs), with fluoxetine being the prototype, followed by sertraline, citalopram, escitalopram, and all of the SSRIs. That’s more the starting point, let’s say, at a family practice level: with somebody who’s presenting with a depressive disorder for the first time and they don’t have any other risk factors, like comorbid conditions, you want to target these symptoms with a single drug.

The general good clinical advice is that the selection of an antidepressant should be decided upon how the person is presented. If you remember, last time when we were talking about depression we said that [we need] a combination of a minimum of 5 symptoms to constitute a depressive episode. But these 5 symptoms could be very different between two people. A 5-out-of-9 combination can give you many different things. For example, depression in one person could be associated with insomnia, poor appetite, agitation, and restlessness, while the other person who’s also been diagnosed with depression will have hypersomnia, overeating, increased weight, and will feel extremely sedated.

Those 2 people cannot have the same drug as a starting point. For the first person, who has insomnia, poor appetite, and restlessness, a very good choice—if you want to avoid polypharmacy—could be, for example, mirtazapine, which is not an SSRI. Mirtazapine has high efficacy in network meta-analyses, when compared as efficacy, and it has the advantages of improving appetite, agitation, and insomnia. It’s a single nighttime dose.

For the person who is more sedated already, eating a lot more, and having lack of energy, perhaps bupropion, which is a class-of-its-own medication, could be more appropriate because it does not have metabolic side effects. It is not associated with weight gain, it increases energy and motivation, and it reduces the need for sleep. So, the context and the patient characteristics can help you with making that first choice.

The other thing with SSRIs—to be kept in mind by all medical specialties—is that these medications are also antiplatelets. For example, in somebody who already has a comorbid medical condition that requires them to be on an antiplatelet, adding that could add a risk of bleeding. Even though it could be the mildest and the most recommended drug, you would not want to give it to somebody who has a history of gastrointestinal (GI) bleed or other risk factors for bleeding tendency.

Roman Jaeschke: This applies to SSRIs?

Zainab Samaan: SSRIs are antiplatelets. Actually they have antiplatelet-like function, they’re not antiplatelets, because they also prevent the uptake of serotonin by the platelets and therefore prevent their aggregation. So they’re added risk.

Roman Jaeschke: You mentioned bupropion. Is it the drug used in nicotine treatment?

Zainab Samaan: Yes. It was first started as a nicotine replacement or cessation [aid], as it helps with reducing craving for smoking. But it has very good antidepressant properties and is very good for depression when people are more sedated, lethargic, sleeping too much, or have increased appetite.

Roman Jaeschke: That's very useful. Anything else we could at this level advise in terms of choices? Is there any place for tricyclic antidepressants?

Zainab Samaan: Yes. Tricyclic antidepressants are still in use and they are really helpful in certain circumstances, if you have a patient who does not have cardiac risk—because they are cardiotoxic and they might be arrhythmogenic as well. Also keep in mind the risk of overdose.

With depression being a disorder associated with suicidal thoughts and feelings that life is not worth living, you want to reduce access to lethal means, and most lethal means would be medications. In a lot of the studies we’ve done and in a lot of studies that are published the most common way of suicide attempts or suicidal behavior is overdose. People reach out for the medications they have. Tricyclics can be quite lethal, so to avoid giving them to someone who is suicidal is a really good idea. They do have a place, though, in the case of a patient who needs sedation for sleep, doesn’t have cardiovascular risk factors, and cannot tolerate, let’s say, an SSRI because of a bleeding tendency or other things, or in patients who have other pain conditions. Tricyclic antidepressants have been used for people with migraine or headaches because SSRIs also exacerbate headaches and you want to avoid that. Tricyclics also have sleeping benefits because of their sedative effect.

So there is still a place for them. They are still effective medications. Tolerability and side effects are keeping us away from them as a first choice, but they are still widely used.

Roman Jaeschke: I have seen some spectacular effects of low-dose tricyclic antidepressants in people with nonulcer dyspepsia as well.

Hopefully the last question: I occasionally see people who are on a combination of antidepressants. Is it rational behavior or is it trial and error?

Zainab Samaan: It’s a very good question. A lot of the times when people start on an antidepressant as a first trial of a medication many of them do well with a single medication, but many don’t.

As specialists, we see more of the severe end of the spectrum of the patient, while perhaps our family medicine colleagues might start with patients at the first onset of depression and eventually might seek our advice—although they do carry a lot of very sick patients. When I worked with family health teams, I was really surprised about how much they carry and how much expertise they have. Really impressive.

The recommendation is that if someone has a trial of an antidepressant failed, you will try another antidepressant, trying to avoid polypharmacy as much as possible. If someone failed 2 different antidepressants from 2 different classes for an adequate length of time, they enter into a new kind of depression called treatment resistance. For treatment-resistant depression augmentation strategies will come into place. Augmentation strategies combine different antidepressants together or an antidepressant with another pharmacotherapeutic agent, such as a mood stabilizer or a second-generation antipsychotic. There are also many other combinations, including thyroid hormones and some other things like tryptophan.

Roman Jaeschke: This obviously should happen under supervision and direction of a psychiatrist?

Zainab Samaan: Yes, exactly, because we want to determine whether it is treatment resistance or somebody did not continue with the medication because of a side effect of the drug. Or maybe the drug failed or there is some other reason.

Roman Jaeschke: That is very useful. In a regular depression—if something like that exists—when could one expect the effect? When do we declare failure and how long to continue once the depression resolves? Let’s say it’s the first episode.

Zainab Samaan: It’s a very good question and patients ask that all the time. We also ask how long to give this medication or in what amount. In an ideal situation, in first-episode depression you start the first treatment. In the old days people used to say that it takes at least 2 to 4 weeks before you start to see some benefit from the medication. Now, when we have more studies, we know that within the first week or after 1 or 2 weeks you will notice incremental changes. Some symptoms start to improve gradually, maybe sleep, maybe appetite. Mood comes later.

You reassess after the first 2 weeks to see how people are doing. Then the choices are if there is a partial response or no response. If there’s nothing at all changed, there is a room to go higher with the dose, depending on the circumstances. If there is a partial response, you might want to give it more time, another 2 weeks. Within the first 6 weeks you will have a better way to say whether this trial is working or not, or to make a next decision. If after 6 weeks things are working well and this is a first-episode depression, the recommendations are to stay with the treatment at the minimum therapeutic dose, balancing side effects versus benefits for another 6 months. If people are symptom-free for 6 months and they continue to be well, then maybe consider tapering off slowly, monitoring their mental status for a few weeks, and then that will be great and you’ll no longer need it.

But if you have a recurrent depression or the severity was so high that someone was acutely suicidal, needing hospitalization, and their life was significantly impacted, then the recommendations are that if you continue on the medication, you need more time. If it’s the first episode, it may be 12 months, and then you may consider tapering off. And if it’s recurring depression, the recommendations are to [continue the treatment] for a long time, maybe forever, to avoid a relapse, because there is ~50% chance of relapse without the treatment.

Roman Jaeschke: Well, that’s useful, taking into account how many patients are taking antidepressants. Thank you very much for this part.

In the next section I would like to talk to you about cognitive behavioral therapy (CBT) and other forms of psychotherapy. Thank you very much for now.

Zainab Samaan: Thank you.

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