Johann Hari’s Dubious Case Against Antidepressants

Lost Connections is sloppy and riddled with inaccuracies

The actual content of Lost Connections: Why You’re Depressed and How to Find Hope by Johann Hari is less self-help than the title would suggest. If I had to summarise my main takeaway from this book, I would say this: People are mostly depressed because their lives are bad. Lost Connections is about how antidepressants are wildly overprescribed, and how Big Pharma has marketed them as a panacea using dodgy science while ignoring the complex social and economic roots of depression and anxiety. 

Hari is above all a sloppy writer, and I have many problems with his book. Doing background research about the book reveals the depths of its issues. Hari has been frequently criticised for misrepresenting research, editing the Wikipedia pages of his detractors to discredit them, and plagiarism. Stylistically, the most annoying feature of Hari is that everything – even the milquetoast scientific consensus – is presented as a mind-blowing revelation. The psychologist Stuart Ritchie had this to say about him:

Hari’s irritating, breathless style turns every single fact he “discovers” into a startling revelation, every single expert he speaks to into the absolute best in the world.

Alas, this book received plaudits from all manner of celebrities and prestigious institutions including Elton John, TED and The Guardian (of course). Is there no justice in this life? Well, I don’t know about that. But there is certainly no justice in the world of pop psychology publishing. 

What is depression, anyway?

People sometimes say that depression is a “chemical imbalance” – usually, a lack of serotonin. This is mostly nonsense. It’s unclear what it would even mean for the brain to be in a state of “chemical imbalance”. Also, while serotonin is known to have something to do with depression, it’s not a straightforward relationship: if you give a chemical cocktail to normal people which lowers their serotonin, they don’t get depressed. Also, tianeptine is a common antidepressant in Europe that works by lowering your serotonin. Some claim that psychiatrists used to believe in the “chemical imbalance” theory but have since moved on. This seems like a strawman and I can’t find evidence of it ever being widely believed.

There is also confusion over whether depression is psychological or physical. The brain is physical, and its behaviour is completely determined by the laws of physics. So, in a trivial sense, everything is equally physical. What it means to call something ‘psychological’ is quite philosophically complex. It means something like this: there are multiple emergent levels of reality. For instance, atoms are real, and presumably, chairs are real too. Something can be considered psychological insofar as it’s more parsimonious to consider it with respect to the mind & consciousness level of reality, rather than the cells & biology level of reality.

There are two extreme ways of looking at depression. One is that it is caused purely by one’s thoughts in a way that is entirely divorced from the physical world – this is the naive view Hari attributes to most doctors in the past. Another is that depression is “just” like a physical illness and should be treated as such. I hear people say this sometimes, and one of their motivations, I gather, is that if people think of mental illnesses in much the same way they do, say, cancer, then there wouldn’t be such a stigma surrounding it. But Hari points to research showing that things actually become more stigmatised when they are thought to result from unchangeable biological characteristics rather than development (Mehta 1997). Ethan Watters discusses stigma in his NYT piece The Americanization of Mental Illness. He points out that, while the social acceptance of many forms of mental illness has grown, for others acceptance has actually fallen:

At the same time that Western mental-health professionals have been convincing the world to think and talk about mental illnesses in biomedical terms, we have been simultaneously losing the war against stigma at home and abroad. Studies of attitudes in the United States from 1950 to 1996 have shown that the perception of dangerousness surrounding people with schizophrenia has steadily increased over this time. Similarly, a study in Germany found that the public’s desire to maintain distance from those with a diagnosis of schizophrenia increased from 1990 to 2001. Researchers hoping to learn what was causing this rise in stigma found the same surprising connection that Mehta discovered in her lab. It turns out that those who adopted biomedical/genetic beliefs about mental disorders were the same people who wanted less contact with the mentally ill and thought of them as more dangerous and unpredictable. This unfortunate relationship has popped up in numerous studies around the world. [A] study, which looked at populations in Germany, Russia and Mongolia, found that “irrespective of place . . . endorsing biological factors as the cause of schizophrenia was associated with a greater desire for social distance.”

On the flip side, there is the worry of concept creep: when people have a term for something, the set of phenomena that it refers to tends to grow over time. What appears to be a mental health crisis could just be a broader class of symptoms being regarded as mental illnesses.

We know from adoptive twin studies that the heritability of depression is 40-50%. When I mention the “biological” causes of depression, you probably think of sleep, diet and exercise. But there are other more obscure factors: people sometimes get depressed as a side effect of medications to treat unrelated conditions, or because they’ve been exposed to lead. Some people’s depression goes away after they start using really bright light bulbs.

Antidepressants are complicated

For most people who take antidepressants, it’s hard to tell whether or not they’re working. But anecdotally, for some subset it helps substantially and is sometimes utterly life-changing. Given this, you would expect that, in clinical trials, you would see a moderate effect size from antidepressants. But depending on how you measure it, the effect size is fairly small (smaller than placebo). Antidepressants look weaker when measured with formal instruments – as Irving Kirsch does; we’ll come back to him – rather than patient preferences. Patient preference is a form of self-report, which is notoriously scientifically dubious, but this is one of the rare circumstances in which self-reports are probably fine. The point is to get people to feel better. 

How do we square small effect sizes with the anecdotal reports? Part of the answer is the variance of outcomes. Antidepressants will work for about half of people, and for those people, they will have a large real effect size. Of the remaining half, some get worse on the pills. These studies are averaging across an entire group, hence why we see a smaller than expected effect size. There are also more technical points about study design – for instance, if the study is not of first-time takers, then those individuals with particularly intractable depression will be overrepresented among the participants. Another part of the answer is regression to the mean: people are likely to seek out medical help for depression when they are at a low point of their lives, and so things will likely get better due to pure chance, which patients (and their doctors) may well think is an actual effect of the drug. When people talk about the placebo effect, they really mean two things: some mysterious psychological force whereby the expectation of something causes it to happen, and regression to the mean. There is a fascinating body of evidence suggesting that, often, this get-better-anyway effect is larger than the bona fide placebo. These important statistical points get only a brief and dismissive mention in the book. 

We have good evidence that antidepressants are very helpful for some people. Plus, even if it’s mostly a placebo, that’s still worth it as long as people feel better, right? Well, Hari says, this might be correct if it weren’t for the very real side effects. Antidepressants have the usual side effects you might get from any drug, like nausea and fatigue. Around half of users also get some form of sexual dysfunction. Sexual side effects are particularly common among takers of selective serotonin reuptake inhibitors (SSRIs), the most common type of antidepressants. The drug companies that produce these medications have a strong incentive to exaggerate their efficacy and downplay the severity of the side effects. And as we’ll see, the side effects of long-term antidepressant use are not well understood.

The number of people that Hari claims take drugs for psychiatric problems is pretty shocking: In the US, 20% of adults are taking a psychiatric drug, 25% of middle-aged women are taking an antidepressant, and 10% of boys in high school are using prescribed stimulants to help them focus. Hari’s numbers are so high that I don’t believe them. The US government says that antidepressant usage is 10%, although the figure for middle-aged women is, alarmingly, basically accurate. Hari never says what counts as a “psychiatric drug”. 

The foremost critic of antidepressants is Irving Kirsch, author of The Emperor’s New Drugs. Hari summarises his research like this: the effects of antidepressants are 50% placebo, 25% regression to the mean, and 25% real effect. His arch-nemesis, Peter Kramer, is antidepressants’ foremost defender in psychiatry:

[Peter Kramer’s] first argument is that Irving is not giving antidepressants enough time. The clinical trials he has analyzed—almost all the ones submitted to the regulators—typically last for four to eight weeks. But that isn’t enough. It takes longer for these drugs to have a real effect. This seemed to me to be an important objection. Irving thought so, too. So he looked to see if there were any drug trials that had lasted longer, to find their results. It turns out there were two—and in the first, the placebo did the same as the drug, and in the second, the placebo did better.

It’s appropriate to be flabbergasted that there are (or at least, were) only two studies that lasted for more than eight weeks of a type of drug that 10% of Americans use. [EDIT: I suspect this is not true. Although I can’t pin down exact dates, someone I trust linked me to this and this and said she found it implausible that only two of the trials over eight weeks had been conducted when Hari wrote his book.] Even Kramer doesn’t agree with the current regimen of keeping people on antidepressants for a large fraction of their lives. For context, Hari has a history of depression and had been taking antidepressants every day since he was a teenager:  

Even Peter Kramer had one note of caution to offer about these drugs. He stressed to me that the evidence he has seen only makes the case for prescribing antidepressants for six to twenty weeks.

It’s worth mentioning that antidepressants work best in combination with talk therapy. The ideal is not endless dosing, but trying several pills to see what works, taking that for six to twelve months, and having the energy to change your life circumstances. I mentioned earlier the extreme view that depression is entirely unrelated to the physical world. Hari writes:

Michael [Marmot, the Australian psychiatrist] would walk around the hospital wards and think—all this sickness and distress must tell us something about our society, and what we’re doing wrong. He tried to discuss this with the other doctors, explaining that he believed that with a woman like this patient, we “should be paying attention to the causes of her depression.” The doctors were incredulous. They told him he was talking rubbish. It’s not possible for psychological distress to cause physical illnesses, they explained. This was the belief of most medical practitioners across the world at that time.

Marmot went on to conduct a study that looked at UK civil servants in Whitehall. All of the civil servants studied had similar lives, pay on the same order of magnitude, but massive differences in status, and the extent to which they had control over their work:

After years of intensive interviewing, Michael and the team added up the results. It turned out the people at the top of the civil service were four times less likely to have a heart attack than the people at the bottom of the Whitehall ladder . . . If you worked in the civil service and you had a higher degree of control over your work, you were a lot less likely to become depressed or develop severe emotional distress than people working at the same pay level, with the same status, in the same office, as people with a lower degree of control over their work.

There’s no problem so bad overregulation can’t make it worse

Hari never accepts the conclusion that a lot of his evidence is pointing to: that the government, and other regulatory bodies like institutional review boards, have been slowing progress in mental healthcare for decades. The two most exciting recent developments in the fight against depression are the use of ketamine and psychedelics. Psychedelics were put on Schedule One by the US government, which dried up the research funding for decades. Ketamine is also illegal and extremely difficult to get by prescription, despite its miraculous ability to treat certain intractable forms of depression (but via injection, which limits its reach).

The regulatory environment seems to be in a worst of all possible worlds situation.  Drug companies’ desperation to show that their drug works results in byzantine regulation to stop them defrauding and exploiting, but the government itself won’t cough up the money to just test what actually works. Hari writes:

When [a drug company] wants to conduct trials into antidepressants, they have two headaches. They have to recruit volunteers who will swallow potentially dangerous pills over a sustained period of time, but they are restricted by law to paying only small amounts: between $40 and $75. At the same time, they have to find people who have very specific mental health disorders—for example, if you are doing a trial for depression, they have to have only depression and no other complicating factors.

Hari points out that there are basically zero large clinical trials that test the major antidepressants against one another, through a weird market failure where no one has an incentive to do this. [EDIT: It has been pointed out to me that this sentence is misleading. There are many trials that compare antidepressants to one another, but they typically meta-analyse studies that compare single pairs of antidepressants or antidepressants to placebo. A large RCT comparing all the common antidepressants would be preferable, because it would have less opportunity for researcher bias. But few if any such large studies exist, depending on what you count as “large”. Thanks to Saloni Dattani for pointing this out.] Even if the government or a philanthropist wanted to run such a trial, the regulations are such a pain in the ass that they don’t.

Hari claims that other solutions to depression are more effective than antidepressants. Why, then, are they so widely prescribed? His answer is corruption combined with people looking for easy answers. Almost everyone involved has bad incentives: 40% of regulators’ wages are paid by drug companies in the US and that figure is 100% in the UK. It seems that Hari is hinting that regulatory agencies are too liberal when it comes to approving new drugs. But there are many convincing arguments that the FDA and EMA are too conservative. A priori, it would be surprising if drugs were approved too quickly on average. Regulators face much harsher consequences for pursuing a policy that actively harms rather than by making an omission that leads to people being harmed.

Why are we getting more depressed?

Johann Hari takes it as a given that people today are more depressed than they used to be. I’m not so sure. Suicide is declining almost everywhere, in some places massively so – a fact that he conveniently forgets to mention. The past was pretty crap. Insofar as his premise is actually true, he offers multiple possible explanations. The first is that we’re more materialistic:

[A] social scientist named Jean Twenge . . . tracked the percentage of total U.S. national wealth that’s spent on advertising, from 1976 to 2003—and he discovered that the more money is spent on ads, the more materialistic teenagers become.

Note that Twenge’s work is far from universally respected. Hari is terrible at summarising studies – both because he uses vague language in describing them, and because he omits details contrary to his narrative. Regardless, it’s plausible to me that advertising makes teenagers more materialistic. Advertising is, in a way, a business model based on making you feel insufficient. Materialism doesn’t make people unhappy by itself, but it makes them more concerned with extrinsic goals like wealth, and less concerned with intrinsic goals like fulfilling relationships:

The results, when [the psychologist Tim Kasser] calculated them out, were quite startling. People who achieved their extrinsic goals didn’t experience any increase in day-to-day happiness—none. They spent a huge amount of energy chasing these goals, but when they fulfilled them, they felt the same as they had at the start. Your promotion? Your fancy car? The new iPhone? The expensive necklace? They won’t improve your happiness even one inch. But people who achieved their intrinsic goals did become significantly happier, and less depressed and anxious . . . Twenty-two different studies have, in the years since, found that the more materialistic and extrinsically motivated you become, the more depressed you will be.

A second explanation is that we’re lonelier:

What [John Cacioppo] wanted to know was—would isolated people get sicker than connected people? It turned out that they were three times more likely to catch the cold than people who had lots of close connections to other people . . . What John’s experiment found was later regarded as a key turning point in the field. The people who had been triggered to feel lonely became radically more depressed, and the people who had been triggered to feel connected became radically less depressed . . . It turned out that—for the initial five years of data that have been studied so far—in most cases, loneliness preceded depressive symptoms.

The evidence appears to be pretty good that loneliness does in fact cause depression, rather than people getting depressed for some other reason and becoming lonelier. The increase in loneliness and decline in social capital, most particularly in America, has been well-documented, most famously in Robert Putnam’s Bowling Alone. The amount of time people spend with their families has dropped, and these trends are true in most of the developed world. This is not necessarily evidence of increased loneliness, because loneliness is not the same thing as being alone. Indeed, Hari says that the correlation between how many people you know and speak with, and how lonely you feel, is quite weak.

It’s obvious that Hari is unreservedly left-wing, and he identifies much of this decline in social capital with the excesses of post-1970s neoliberalism. The mechanism for this isn’t made clear. He has an obligatory dig at Margaret Thatcher and approvingly cites an example of people improving their mental health via community organising . . . to lobby for rent control.

Depression as grief

If your mother dies, we might say it’s “justified” for you to feel depressed for a while, but if your life is going fine but for some reason you feel terrible all the time, that’s “unjustified” and therefore should be treated. Where do we draw the line between a normal reaction to tragic things happening in your life and bona fide mental illness? Hari writes: 

After you lose (say) a baby, or a sister, or a mother, you can show these symptoms for a year before you are classed as mentally ill. But if you continued to be profoundly distressed after this deadline, you will still be classified as having a mental disorder. As the years passed and different versions of the DSM [Diagnostic and Statistical Manual] were published, the time limit changed: it was slashed to three months, one month, and eventually just two weeks.

Hari then mentions how, in the DSM-V, the latest version, this proviso has been eliminated and you can be diagnosed with depression irrespective of your life circumstances. Hari hints that this is because the people who write the DSM are robots who don’t understand that humans sometimes feel negative emotions in response to bad events. Hari conveniently forgets to mention that the DSM makes a deliberate (albeit, controversial) decision to prescribe entirely on the basis of symptoms and not on the basis of aetiology. The benefit of this is that we can just list what the symptoms are of certain mental illnesses and what has helped to treat them, rather than allow psychologists to become arbiters of what counts as a “reasonable” or “proportionate” emotional response to different life events. We’ll leave that to the philosophers.

There is a kernel of truth here, which is that psychologists and psychiatrists have historically not given sufficient attention to how people’s life problems arise from their circumstances, diet, exercise, sleep, and so on. But this is a matter of emphasis; obviously, no one believes in Hari’s straw man. Hari’s own experience of the medical system seems to be particularly bad in this respect:

As [the researcher Joanne Cacciatore] said this, I told her that in thirteen years of being handed ever higher doses of antidepressants, no doctor ever asked me if there was any reason why I might be feeling so distressed. She told me I’m not unusual—and it’s a disaster.

The solution to this dilemma was to divide depression into reactive depression (in response to life events) and endogenous depression (that comes on for seemingly no reason). Needless to say, this dichotomy has been quite problematic, mostly because the things someone is reacting to with their depression can be subtle:

George [Brown] and Tirril [Harris] explained that they had, all along, been studying women who had been classified by psychiatrists as having “reactive depression” and women classified as having “endogenous depression.” And what they found—when they compared the evidence—is there was no difference between them. Both groups had things going wrong in their lives at the same rate. This distinction, they concluded, was meaningless.

To be fair, Hari talked to a number of people about endogenous depression, and they gave a range of answers, ranging from thinking the distinction is meaningless to thinking that endogenous depression is real but makes up a small subset of depressives. An implicit premise here is that endogenous depression should be more effectively treated by antidepressants than exogenous depression. But “There is currently no strong evidence for or against the claim that SSRIs treat endogenous depression better than they treat exogenous [depression]”. Even the psychiatrists themselves do not believe that their drugs should work especially well against endogenous depression; why then is Hari concerned with it?   

Magic pills and bad incentives 

Hari is great at pointing out the extent to which we do not currently have a pill that you can take that will reliably make you magically happier. But he fails to appreciate how amazing it would be if we did, and how this should be a top priority for science. A quote from Joanne Cacciatore sums up Hari’s position pretty well:

Our approach today is like putting a Band-Aid on an amputated limb. [When] you have a person with extreme human distress, [we need to] stop treating the symptoms. The symptoms are a messenger of a deeper problem. Let’s get to the deeper problem.

I get this at an individual level. People want easy answers. They don’t want to be told that they’ve made many bad life choices that will be difficult to undo, or that they need to lose weight or get better friends. Or worse yet, that their woes are a necessary consequence of free trade and capitalism. Maybe this is just because Hari and I inhabit different worlds, but if anything, at a social level this is the opposite of the attitude that we normally take. Most people are far too quick to jump to the conclusion that there must be something wrong with society, and vehemently try to avoid the possibility that there is something wrong with them. Once upon a time, I wrote an article that argued that prestigious universities should use a partial lottery to allocate places. I no longer endorse this, but nonetheless, the most common response was that this would only be a bandage on the true problem, and that to really fix this, we would have to invest in education and eliminate the discrepancies that led to the privileged being so overrepresented in elite universities. From my perspective, it seems like people are absolutely desperate to go on multi-decade long questionable social engineering projects, and they don’t want to put bandages on problems enough.

The old way of thinking was to blame depression on personal failure. The new way of thinking is to blame it on nature. Hari wants us to blame nature less and society more, and he doesn’t say much about the personal failure part. I’m sceptical of efforts to blame it on any of these, and I think it’s more like we’ve been bequeathed with a tragic mismatch between all three.

Antidepressants are probably overprescribed in America, and about other countries I am less certain. This is almost certainly because of doctors having bad incentives. I suspect the optimal rate of antidepressant usage is rather high; pills are hundreds of times easier and cheaper than talk therapy and other complex interventions. If your doctor were actually incentivised to make you healthy, healthcare would look very different. They’re incentivised to make you relatively healthier while minimising the risk of malpractice lawsuits and not offending you or your parents too much. If a parent comes in describing how their teenage son is feeling depressed, the correct response may well be to point out how it would be a miracle to have such an annoying mother and not be depressed. But given the incentives the doctor faces, the correct response is to just shut up and prescribe him Zoloft. Maybe I should get in while the market is young and start selling t-shirts that say “Shut up and prescribe Zoloft”.

Johann Hari has not written the worst book in the world. He has not even written the worst book on depression. I struggle to rile myself up about his doling out of reckless advice, since it goes without saying that a popular psychology book isn’t medical advice. But it does make me sad that such a large audience lap up Hari’s books uncritically. Not quite depressed, but sad.