This isn't professional medical advice, it's just my experience and amateur knowledge. 

Summary

• I got moderately (and occasionally, severely) depressed about four months into the pandemic. 
• I tried a bunch of things to treat it, including therapy, antidepressants, meditation, and a long list of other things.
• I was prescribed the antidepressant sertraline (aka Zoloft) by my NHS GP, and it really helped! But it had a number of side effects that made me very unexcited to stay on it.
• I experimented with a bunch of different types of antidepressants to see if I could find one that worked well and didn’t give me bad side effects. 
• I knew this would probably be a long and grueling experiment... and it was. It took over a year, and was really hard, both emotionally and physically. 
• But I ended up finding a great one for me, and it now feels well worth the costs. 
• I think this kind of experimentation might be a good approach for some people who also experience depression and anxiety.
• Caveats:
  • This was expensive. It’s probably much harder to do this without savings or great insurance, or both. 
  • I have a particularly supportive work environment and partner. It’s probably much harder to do this without those things.
  • Things besides antidepressants were also really important to feeling better (and also allowed me to stick with the experiment). Therapy and cognitive behavioral therapy (CBT) were extremely effective for me in treating my imposter syndrome and perfectionism, and in making my depression manageable. Searching for an antidepressant that worked for me probably wouldn’t have gone nearly as well if I hadn’t done it alongside these other practices.
  • Antidepressants have not solved all of my problems — and it’s important to set reasonable expectations for how much they can help. 

Context

I got moderately (and occasionally, severely) depressed about four months into the pandemic. 

This was triggered by: 

• The pandemic — including things like: feeling very isolated, not having much personal space, shitty British weather, having to work from home, not being able to see my family for years. 
• Genetics — my mom has suffered from moderate-severe depression since she was in her early thirties.
• Imposter syndrome at work — I’d gotten a dream job, but it felt like, sooner or later, my employer would realize I was a total phony. I was afraid to do really any task that might reveal I was actually a big idiot, which made me anxious for a lot of my day-to-day activities. 

My main symptoms were: 

• Having continuous low mood or sadness
• Feeling hopeless
• Having very low self-esteem, feeling like I was letting everyone down all the time
• Feeling tearful
• Feeling guilt-ridden
• Feeling irritable and intolerant of others
• Having little motivation or interest in things — finding myself and everyone else really boring
• Finding it difficult to make decisions
• Not getting much enjoyment out of life, including out of things that were previously some of my favorite activities (hiking, seeing close friends) 
• Feeling anxious and worried

Non-pharmacological things I did to treat my depression:

• Weekly therapy with an excellent therapist, who taught me a bunch about CBT (helped a lot)
• Weekly therapy with a couples therapist (sometimes my depression made me especially angst-y about my relationship) (helped a bit)
• Taking time off work (sometimes helped, sometimes made things a bunch worse)
• My depression was a factor in switching jobs (kind of helped)
• Changing my role at work significantly to focus on tasks I found especially exciting and satisfying (helped a lot)
• Spending time in sunnier countries (helped a fair bit) 
• Regular exercise (helped a fair bit when I actually had the motivation to do it)
• Meditation (unclear if it helped)
• Kept a gratitude and positive-self-talk diary (maybe helped a bit)
• Bright lights at my desk and indoor tanning for seasonal affective disorder (unclear if it helped)

These things helped a bit, but not enough to make a dent in my worst symptoms. I had a strong feeling that there was just some basic chemistry going wrong in my brain that was “shifting all of my experience down” — making things I used to enjoy unenjoyable, and things that used to feel kind of hard feel intolerably bad. 

My GP and therapist agreed and encouraged me to try an antidepressant.

I was prescribed the antidepressant sertraline (aka Zoloft) by my NHS GP, and it really helped! But it had side effects:

• Insomnia
• Anorexia (especially at the beginning)
• Stomach problems (really bad ones)
• And what the field of psychiatry calls “sexual dysfunction”

I won’t say much about the details of these, but I will say: I didn’t take these side effects very seriously for a long time, despite the fact that they were making my day-to-day life a lot shittier in some ways. I thought: What right do I have to complain about e.g. sleeping badly, when the alternative is depression? If I went off these, I’d be sad again, which would make it hard to work — I can’t jeopardize my work just because of these. 

It was hard for me to come to terms with the fact these were real and serious issues, and that it wasn’t “irresponsible” or “selfish” of me to try to treat my depression in a way that didn’t reduce my life satisfaction in other areas of my life. 

When I eventually did come to terms with that, I decided to try going off sertraline. And then got very depressed again.

The idea: experimenting with a bunch of antidepressants

I explained all of this to one of my colleagues, Howie Lempel, who lots of people will know is just extremely thoughtful and wise about mental health.

Howie suggested I see a psychiatrist (rather than an NHS GP), to learn about other classes of antidepressants, and try a bunch out to find out which actually worked best.

I was very, very opposed to this idea. Going on and off antidepressants was really hard for me. When I started taking them, I had such bad side effects I had to take time off. And when I went off them, I had brain fog and “brain zaps,” both of which are really uncomfortable and frustrating. Plus, it can take up to four weeks to know if an antidepressant is working for you, so trying several takes many months.

Howie countered:

1. The upside potential for a person with a predisposition for depression could be huge: spending three to twelve months of my life going on and off antidepressants, while horrible, would be so incredibly worth it if I ended up finding an antidepressant that made me happier and more resilient without ruining my sleep and destroying my digestion.
2. The sooner I found the right antidepressant for me, the more years of Feeling Happy I would get to have over the course of my life — hopefully another 60+ years. So a huge deal, and one that I think lots of people don’t fully appreciate when deciding whether to try to address the problems in their lives now or put it off. 
3. And reminded me I’m currently lucky enough to have very supportive employers, who would support me with both my mental health expenses and in taking time off if necessary. 

And I was convinced. 

So I got a psychiatrist and started learning about antidepressants.

What I learned about antidepressants

• There are so many! I’d only really heard of the selective serotonin reuptake inhibitors (SSRIs) (and Wellbutrin aka bupropion, because of Rob Wiblin’s blog post on the topic) — but there are a bunch of other types: serotonin-noradrenaline reuptake inhibitors (SNRIs), noradrenaline and specific serotonergic antidepressants (NASSAs), tricyclics (TCAs), serotonin antagonists and reuptake inhibitors (SARIs), and monoamine oxidase inhibitors (MAOIs).
• And different ones seem to work for different people, and they have pretty varied side effect profiles.
• It’s really hard to predict which will work for you! Very little is known about why some people respond better to some antidepressants while other people respond better to others. And while you can do genetic testing to try to get a bit of additional evidence about which antidepressants might work best, it’s not super accurate yet — plus, it’s expensive and doesn’t tell you anything about which drugs are likely to give you side effects. 
• But research on antidepressants can help.

I’m not going to do a full literature review here, but I wanted to highlight the meta-analysis my psychiatrist and I used to decide which antidepressants to try and in what order. Here are the headline findings from the “head-to-head studies” — which compare treatments to each other, rather than just comparing treatments to a placebo:

Effectiveness: 

In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs [odds ratios] 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84).

Acceptability (how “acceptable” is the drug — how bad are the side effects, measured by dropout rates):

For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

The evidence for drugs with smaller sample sizes is weaker than the evidence for drugs with larger sample sizes. The size of the circles in the diagram below represent the number of randomly assigned participants in all of the studies included in the meta-analysis. The width of the lines is proportional to the number of trials comparing every pair of treatments. So those with the biggest circles and the thickest lines have the strongest evidence base.

The graph below brings these two factors (effectiveness and acceptability) together^[1] — top right is good, bottom left is bad:

My experiment

1. Start with the SSRIs — they seem to work for lots of people, and very easy to get from a general doctor.
2. Then, with the help of a psychiatrist, try as many antidepressants as it takes to find one that both helps me, and doesn’t give me loads of side effects. 
3. Start with the antidepressants with the fewest side effects.
4. Start with the lowest possible dose to see if I can get an effect on my depressive symptoms while reducing the chance of side effects.
    

With this in mind (and using the handy chart above!), my psychiatrist and I developed an ordered list of which antidepressants to try:

1. Sertraline (Zoloft) 
2. Bupropion (Wellbutrin) 
3. Fluoxetine (Prozac) 
4. Citalopram (Celexa) 
5. Agomelatine (Valdoxan) 
6. Vortioxetine (Brintellix)
7. Reboxetine (Edronax)
8. Venlafaxine (Effexor)
9. After that… come back to the drawing board.

And we used these guidelines for switching between specific antidepressants to figure out how to transition from one to another. 

The results

I tried a total of six drugs (some at several doses) over the course of a year and a half. 

There were lots of ups and downs associated with going on and off these drugs:

 

But overall, I was able to find an antidepressant (vortioxetine) with much more manageable side effects, and overall, I feel much happier than I was in 2020 and 2021.

I don’t feel “done” — I’m not happy all the time, and there are still emotional bumps in the road of my recovery. 

There’s definitely still some room for improvement, but I’m happier than I’ve been in a long time, and I no longer score in the clinical ranges on depression. I tracked all this progress as part of the experiment, which you can see in the graph below — lower scores are better, as they indicate fewer symptoms of anxiety and depression. 

The hardest parts of this, and what got me through

The hard parts

• This sucked. It was extremely difficult to stick to this plan. Staying depressed for a long time, when it felt like I could just go back on some side-effect-y SSRI and feel somewhat normal, was terrible.
• This affected my job (e.g. sometimes the side effects of going on a new antidepressant forced me to take time off work) and my relationship (e.g. I was sometimes much more emotionally turbulent than my partner was used to).  
• Going on and off some of these was BRUTAL: a week or two of nausea, stomach problems, insomnia, tearfulness, and depression getting WORSE rather than better. These were some of the biggest costs, and while I was experiencing them, I often felt like my approach wasn’t worth the costs.  
• Antidepressants have not solved all of my problems. Again, I’m not happy all the time… I still feel social anxiety, work stress, and sadness a fair bit, and I still catastrophize about things — but I've learned a lot of healthy ways to deal with these tendencies (more on this below). 
• This was expensive. I had to meet with a private psychiatrist a bunch of times (£££), and I paid for the drugs out of pocket because it was a lot faster than going through my GP — I think I wouldn’t have been able to do this if I’d been in the US. I recognize this could very well make experiments like this prohibitively expensive for lots of people. If I were to try to do it more cheaply, I’d ask to be prescribed generics (which can take longer / involve more faff), and go through a GP for the more traditional medications (SSRIs, bupropion if in the US). 

What got me through

• Having a therapist who knew my plan, supported it, and helped me get perspective when I lost sight of why I was subjecting myself to the plan.
• An extremely supportive partner, plus supportive friends who knew about my experiment, and with whom I was very open about my symptoms and side effects.
• I was lucky that my workplace was extremely supportive of me spending time, money, and energy to improve my mental health. I told my manager about my plan, and got tons of support and understanding from her throughout my experiment (e.g. she was encouraging and understanding even when going on and off different drugs made it especially hard to work normal hours). 
• Things besides antidepressants were really important to feeling better (and sticking with the experiment). Therapy and CBT were extremely effective for me in treating my imposter syndrome and perfectionism, and in making my depression manageable. 
• Writing a note to myself I could read when I felt especially down:
  Remember: Until [e.g. October 25th], you might feel especially sad. But it’s not going to be this way forever. You’ll get through it and then you’ll feel as happy as you did in late September. Remember that? That was fucking great. That’s very achievable again! You’ll have it back, just gotta be patient and kind to yourself for a bit longer. 
   

1. ^{^}

   "Data are reported as ORs in comparison with reboxetine, which is the reference drug. Error bars are 95% CrIs. 

   Desvenlafaxine, levomilnacipran, and vilazodone were not included in the head-to-head analysis because these three antidepressants had only placebo-controlled trials."