Book Review: Lost Connections

The actual content of Lost Connections: Why You’re Depressed and How to Find Hope by Johann Hari is significantly less self-help-y than the title would suggest. If I were to summarise my main takeaway from this book, it would be 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 depression and anxiety. There are parts of the book that I liked, but I have some problems with it.

What is depression, anyway?

One of the things people say about depression is that it’s a “chemical imbalance” – usually, a lack of serotonin. Needless to say, this is 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 which 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.

So that’s one confusion about depression. Another is about the extent to which depression is psychological vs. physical. Of course, 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 actually 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 this kind of language from people sometimes, and one of the motivations for saying this, 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. I discussed this research (Mehta 1997) with friends recently, and the best explanation anyone could come up with was that humans are tribal, and people who are genetically or biologically different to us are an out-group, whereas those who had bad things happen to them or fall into a negative cycle may well be in our in-group. The next step would be to check whether congenital conditions get less funding relative to the proportion of the disease burden they represent.

Ethan Watters discusses stigma in his excellent 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. So, what appears to be a mental health crisis could just be a broader class of symptoms being regarded as mental illnesses. Concept creep is, in a way, what happens when there isn’t enough stigma – at least, enough stigma surrounding carelessly diagnosing oneself or others with a mental illness.

So, there are downsides to couching depression in biomedical language, but it is of course to a large extent biological. We know from adoptive twin studies, for instance, that depression and anxiety are 30-40% genetically determined. 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, and their depression sometimes goes away after they start using really bright lightbulbs.

Antidepressants (mostly) don’t work

Anecdotally, for most people who take antidepressants, it’s hard to tell whether or not they’re working. But 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 nope: you see a tiny one that is frequently indistinguishable from placebo. (Side note: effect size is frequently mistakenly thought to mean “the size of the effect”. But effect size in statistics is this number divided by the standard deviation, making it a dimensionless quantity.) How do we square this with these anecdotal reports? Part of the answer lies in the variance of outcomes. The rule of thumb seems to be that one third of people have undeniable positive effects from their first antidepressant and two thirds of people eventually get the same from one of the antidepressants that they try. These studies are averaging across an entire group, hence why we see such a small 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 those being studied. Another part of the answer is regression to the mean: people are likely to seek out medical help when they are at a low points 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 studies containing a placebo group, 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 showing that, often, this get-better-anyway effect is much larger than the bona fide placebo.

So, the evidence for the efficacy of antidepressants is quite weak, but we also have these reasons to believe that they’re somewhat helpful. 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 of antidepressants. There are the usual side-effects you might get from any drug, like nausea and fatigue, but notably also sexual dysfunction. Sexual side-effects are particularly common among takers of selective serotonin reuptake inhibitors (SSRIs), which is the most common type of antidepressant and what most people think of when they think of antidepressants. The drug companies who produce these medications have a pretty strong incentive for exaggerating their effect and downplaying the severity of the side-effects. Also, as we’ll see, the side-effects of long-term antidepressant use are not well understood.

The number of people who take drugs for psychiatric problems is pretty shocking: 20% of US 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. These 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 introduces us to the foremost critic of antidepressants, Irving Kirsch, author of The Emperor’s New Drugs. Hari summarises his research as concluding that 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:

“[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.”

I think 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. Even Kramer doesn’t agree with the current regimen of keeping people on antidepressants for basically their whole 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.”

Next, Hari talks about 5-HTT, a gene that was thought by the research community to be significant in explaining depression but which, according to this Slate Star Codex piece, turned out to have no effect whatsoever. (This article is about 5-HTTPLR, and I can’t figure out if this is the same thing as 5-HTT. I know very little about biology and I can’t understand the first few links on google.) Hari says that 5-HTT, and other genes that are risk factors for depression, work by multiplying the risk of depression in response to negative life events, raising the probability of a depressive episode following a major negative life event from (say) 15% to 20%. I would be interested to see how people’s genes cause them to shape their environment differently, thus making negative life events more or less common.

I mentioned earlier the extreme view that depression is entirely unrelated to the physical world. He 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. Anyone can notice that the poor and those with difficult and unpleasant jobs tend to have worse mental and physical health. But this could be for lots of reasons. All of the civil servants studied had somewhat similar lives, pay on the same order-of-magnitude, but massive differences in status, and the extent to which they had control over their jobs:

“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 appears to be 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 schedule 1’d 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 (via injection) intractable forms of depression.

The regulatory environment seems to be in a worst-of-all-possible worlds situation, where the fact that drug companies are really desperate to show that their drug works results in byzantine regulation to stop them from exploiting people or defrauding anyone, but the government itself won’t cough up the money to just test what actually works. He 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 which test the major antidepressants against one another, through a weird sort of market failure where no-one has an incentive to do this, and even if the government or a philanthropist wanted to do this, the regulations are such a pain in the ass that they don’t.

If antidepressants were mediocre but there was no alternative, then their frequent usage would be no mystery. The problem is that we know other solutions are more effective. For instance, one of the common scales for depressive symptoms is the Hamilton scale, which runs from 0 (perfect bliss) to 51 (perfect misery). Antidepressants, on average, produce a 1.8-point jump on the Hamilton scale, while having a regular sleep schedule produces a 6-point jump. Hence there needs to be some reason why antidepressants are used in excess of how useful they actually are.

Hari’s answer is corruption combined with people looking for easy answers. Indeed, almost everyone involved has bad incentives: he points out how 40% of regulators’ wages are paid by drug companies in the US, and the figure is 100% in the UK (!). I’m not sure whether he would agree with this, but it seems like he’s hinting that regulatory agencies are too liberal when it comes to approving new drugs. But I’m the kind of person that reads many blog posts arguing that the FDA (and by extension the EMA) is too conservative. Indeed, 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 leads to harm 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 these days are more depressed than they used to be. I’m not so sure; suicide is declining almost everywhere, in some places massively so. The past seemed pretty crap. And yes, self-report studies show mixed results, but self-report studies are almost worthless. Nonetheless, insofar as his premise actually is 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.”

I would hope that there were corrections done in this study to try to show causality. Hari isn’t good at summarising the results of studies, and he frequently uses vague language. Regardless, this seems somewhat plausible. Advertising is, in a way, a business model based on making you feel insufficient. Being materialistic wouldn’t make people unhappy by itself, but the theory would be that it causes people to chase extrinsic goals like wealth and not intrinsic ones like fulfilling relationships, and therefore they don’t get any happier:

“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 consequently withdrawing from society 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 spent with their families has also 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 actually quite weak.

It’s obvious that Hari is quite 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 – maybe the growth of an individualist mindset that is more focused on individual consumer experience than on social experiences like family and church? He has some obligatory digs at Margaret Thatcher and he approvingly gives an example of people improving their mental health via community organising… to lobby for rent control.

Depression and 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. So, where do we draw the line between a normal reaction to tragic things happening in your life, and bona fide mental illness?

“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 were published, the time limit changed: it was slashed to three months, one month, and eventually just two weeks.”

He then goes on to mention 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. But 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. Nevertheless, there’s a good point 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. 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 – that many depressed patients were having perfectly understandable reactions to negative life events – was to divide depression into “reactive depression” (in response in 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 in becoming depressed can be quite 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.”

So, is endogenous depression just fake news? Maybe. 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.  

Conclusion

Hari is great at pointing out the extent to which we do not currently have a pill that you can take that will make you magically happier. But I think 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 Joanna Cacciatore sums up his position pretty well:

“Our approach today is, Joanne said, “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 societal level this seems like the opposite of the attitude that we 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. On my old blog, I wrote a piece that argued that prestigious universities should use a partial lottery to allocate places. I’m not sure whether I particularly 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 rich and 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 almost certainly overprescribed, and this is almost certainly because doctors have bad incentives. 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 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”.

Thanks for Gytis for reviewing a draft of this piece.

One thought on “Book Review: Lost Connections

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