Reviewing the evidence for the biological basis of depression
By Conrad Taylor MNCPS Acc
According to the World Health Organisation, depression is “characterised by persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities”. (www.who.int, 2024). The WHO continue by saying that around 5% of the world’s population suffer with this disorder. For someone who is struggling with the daily challenges of depression, I am not sure that this definition goes far enough to encapsulate the disorder. Depression is multi-layered, complex, has different levels of severity and for some people can be a debilitating condition that limits their ability to function in life; existence becoming a daily toil. Given that human kind has battled with depression for as long as we have been conscious beings, the opportunity to find a ‘cure’ would have huge positive consequences for civilisation.
Up until the 1950’s, depression was mainly treated by psychotherapy and/or by hiding a person away from society in mental institutions. With the gradual post-war rise in pharmacology, scientists in the 1950’s who were treating tuberculosis with a drug called Marsilid (Hari 2019, p33)discovered that whilst it did nothing for TB, the medication had a positive effect on improving patients’ moods and levels of depression. “It made the patients gleefully, joyfully euphoric”. (Hari 2019, p34). Other drugs with similar outcomes came along – Ipronid and Imipramine – and these were used to treat people with depression. No-one really understood why they worked until a British doctor called Alec Coppen in 1965 tentatively put forward a theory that these medications improved the uptake in serotonin and other neurotransmitters in the brain. This was the start of the biological theory that depression and low moods were caused by a lack of serotonin and/or norepinephrine. The medical profession proposed that by increasing either or both of these neurotransmitters, depression could be alleviated. This hypothesis was further supported by another drug called reserpine that seemed to reduce serotonin levels and, alongside this, patients taking this particular medication were prone to low moods. In other words, it was hypothesised that depression/low moods were as a result of low levels of serotonin/other neurotransmitters and the solution was to increase their uptake. These early medications were not administered to many patients; only those with chronic depression because they had severe side-affects. But the theory that depression was caused by a chemical imbalance remained in the medical community, and this would be the starting point for new medications that came into existence in the late 1980’s and subsequently became the dominant treatment for depression. “For three decades, people have been deluged with information suggesting that depression is caused by a ‘chemical imbalance’ in the brain – specifically an imbalance in serotonin”. (Moncrieff & Horowitz, 2022)
A key development that took place in the 1970’s acted as a springboard for significant growth in the pharmaceutical sector and the development of new medications. This was the introduction of the Diagnostic and Statistical Manual of Mental Disorders (DSM) by Robert Spitzer. At the time, the reputation of the psychiatric community was under scrutiny and the DSM was designed to standardise different psychiatric diagnosis and treatments that were backed up by empirical evidence. Although the DSM has garnered much controversy and criticism for its arbitrary approach, it created an opportunity for the pharmaceutical industry to develop medications that were aligned to specific disorders. Depression was one of these disorders to receive much attention from the drug companies.
In the late 1980’s, Eli Lilly launched Prozac – the first Selective Serotonin Reuptake Inhibitor (SSRI). The drug was based on the previously discussed early biological theories around depression being the result of chemical imbalances and, as a result, Prozac boosted the amount of the neurotransmitter serotonin. Johann Hari is a published journalist who has suffered with depression most of his life and this led him to research the causes of depression. In his book, Lost Connections (2019, p8), Hari recollects advice he received as a young adult, from his doctor. “There are some people who naturally have depleted levels of a chemical named serotonin in their brains, he said, and this is what causes depression – that weird, persistent, misfiring unhappiness that won’t go away”. Prozac was launched as a wonder drug that would revolutionise people’s lives and it was supported by medical research, using randomised controlled experiments, as empirical evidence that it worked. The SSRI drug was written about in the key medical journals such as the Lancet, endorsed by the American Psychiatric Association and was approved by the FDA as a successful treatment for depression. Alongside this, Eli Lilly embarked on a major marketing campaign that led to both doctors, who were prescribing Prozac, and the worldwide population believing the theory that depression was a biological disorder, which could be treated with SSRI’s. Moncrieff & Horowitz (2022) comment that “many people started taking anti-depressants because they believed they had something wrong with their brain that required an anti-depressant to put it right”. According to Wikipedia, US annual sales of Prozac grew to $350M within a year and eventually worldwide sales peaked at $2.6M. During the 1990’s, this led to other pharmaceutical companies developing their own SSRI’s and examples of these are citalopram, paroxetine and escitalopram. In addition, other medications such as venlafaxine and dulozetine were developed as Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs). Although there can be side-effects to both SSRIs and SNRIs, it was considered that these weren’t as bad as the early forms of medication for treating depression, and they could be limited by starting with a low dose with gradual increase. During the 1990’s, these were the go-to treatments for depression and the biological narrative of chemical imbalance was firmly set in the public consciousness.
However, during the 2000’s parts of the medical community started to challenge the rationale behind this biological theory with startling results. One of the first scientists to review the theory behind depression was a professor called Irving Kirsch along with one of his research students, Guy Sapirstein. They never set out to disprove the chemical imbalance theory. Kirsch was more interested in investigating how the placebo worked as opposed to challenging the biological theory for depression. According to the Oxford Dictionary of English, “placebo is a medicine or procedure prescribed for the psychological benefit to the patient rather than for any physiological benefit”. A placebo is used when trialling new drugs to test the effectiveness of the treatment alongside any side-affects. Along with Sapirstein, Kirsch decided to start his study into the placebo effect by focusing on how it works against SSRIs in the treatment of depression. Controversially at the time, Kirsch used the technique called meta-analysis to develop his research. He initially analysed 38 clinical trials including in excess of 3000 patients who were experiencing depression. Kirsch assessed many different studies that had been done around depression with the placebo and making cross-comparisons. Because meta-analysis does not involve any new research, the scientific community were sceptical. However, it should be noted that meta-analysis is now considered a very good way to look at the efficacy of medications. Kirsch was initially puzzled by the outcome of his research, which seemed to show that the placebo performed almost as an equal to the SSRIs. “People obtain considerable benefits from many medications, but can also experience symptom improvement just by knowing they are being treated. This is called the placebo effect”. (Kirsch 2009, p1). If SSRIs are not much more effective than a placebo, this is an issue because of the consequences of taking drugs in terms of side-effects. Kirsch started to widen his research to other SSRIs and the results were the same. In his subsequent book The Emperor’s New Drug, Kirsch discusses his findings and he believed that the studies into SSRIs were further compromised by ‘breaking blind’ of both patients and researcher. Randomised control experiments are a common research approach and are based on a technique called ‘blinding’ where neither the researcher or the patient know whether they have received by live drug or the placebo. However, because of the side-effects of SSRIs, patients were quickly able to realise that they had received the drug and this acted as a double placebo, therefore impacting the results of the study. In other words, if the patient experienced side-affects, they knew they were receiving the medication and this caused them to believe that they would get better. “89 per cent of patients given the real anti-depressants correctly figured out that they were in the drug group”. (Kirsch 2009, p15). In his book Bad Science, Ben Goldacre (2009, p44), “Flaws in trials are actually very common throughout medicine”. He continues, “Every trial will involve a compromise between what would be ideal, and what is practical or cheap”.
These initial findings caused Kirsch and his colleagues to further explore the empirical evidence around the effectiveness of SSRIs. Firstly, most of the trials were by using randomisation trials and Goldacre (2009, p50), notes that this type of experiment in isolation can “overestimate treatments by 41%”. Secondly, because many research studies are not published, it was suggested by a scientist called Thomas J Moore that Kirsch make a request to the FDA under the Freedom of Information Act to have access to all studies into SSRIs whether they were published or not.
Following this more comprehensive analysis, Kirsch uncovered what he called the medical industry’s ‘dirty secret’ (2009). This was that the research supporting the biological theory that depression was based on a chemical imbalance was largely unproven. According to Goldacre (2008), “anti-depressants perform only marginally better than placebo, and the NICE guidelines have actively advised against using them in milder depression since 2004”. Despite the unreliability of the scientific evidence, the pharmaceutical companies had sponsored all research into SSRIs and were guilty of massive publication bias. Only positive studies were published and negative ones were either left out of the public domain or even worse made to look as if the results were more positive than they actually were. Kirsch (2014, p4) comments “I discovered that 40% of the clinical trials conducted had been withheld from publication by the drug companies that sponsored them”. Goldacre (2009, p45) contributes to the debate by saying “It’s important that research is published in full, with its methods and results available for scrutiny. We need to be able to decide for ourselves how big the methodological flaws were, and come to our judgements about whether the results are reliable”. However, with big profits at stake the big pharma companies could not allow this to chance. Goldacre (2012, p205) says “drug company trials are much more likely to produce a positive outcome for their own drug”. As a result, it is claimed that the pharmaceutical industry created the chemical imbalance theory on misleading research, publication bias and by using a huge marketing budget to ensure that the theory was taken up. “Drug companies know the benefits of good branding: they spend more on PR after all than they do on research and development”. (Goldacre 2009, p68). Doctors understandably find it impossible to read all literature/articles relied on the research and began prescribing SSRIs based on this supposed ‘empirical’ evidence further promoted through the extensive marketing campaigns claiming they worked to combat depression. The public also bought into the biological theory and started seeking prescriptions for their depression.
The big pharma companies are not the only ones to have their actions come under scrutiny. It became clear that the FDA and other regulatory bodies were also indirectly complicit in creating this myth by allowing the systematic bias and supporting the actions of the pharmaceutical industry. Here there is a conflict of industry because essentially they are funded by the pharma industry too, impacting on their impartiality. “Pharmaceutical companies fund the majority of studies on anti-depressants and they have a clear financial interest in the success of these drugs.” (Kirsch, 2008).
In summary, Kirsch criticised the accuracy of the research that resulted in the development of SSRIs claiming that this biological theory is not proven. In reviewing the results, Kirsch had seen that the drug companies had hidden some of the data that did not support their theory. Although there were 37 positive research experiments in favour of SSRIs that were published, there were 22 negative studies that were not published and a further 11 that were published but in a form that made them appear more positive than they actually were. In addition, the positive studies were published multiple times leading to duplication bias. Following his years of study, Kirsch claims that his research shows that antidepressants are no better than a placebo but with additional side-effects that are caused by the chemicals in the drugs, which can be severe. There is a risk of suicide in young people taking anti-depressants and in older people there is a higher risk of death from things like strokes. Pregnant women have a greater risk of miscarriage.
Inevitably, the pharmaceutical industry pushed back on Kirsch’s claims and a dispute between different factions of the scientific community started to develop regarding whether SSRIs actually worked or not. Writing in the 1990’s, Dr Peter Kramer was convinced that the SSRIs were working, as he noted the transformation of patient health in his clinic, pointing out that “they had more resilience and energy than the average person”. (Hari 2019, p 40). Kramer wrote many articles and papers criticising Kirsch’s work. His book, Listening to Prozac promoting the benefits of antidepressants, became a best seller. Kramer claimed that Kirsch needed to give anti-depressants more time – the majority of research in his meta-analysis were focused on patients receiving the drugs for 4-6 weeks. He also argued that Kirsch’s analysis did not distinguish between mild and severe sufferers of depression, and that this watered down the results. This latter point was disputed by Kirsch who realised that he had, with one exception, only looked at studies of people with severe depression. Hari (2019, p42) continues describing Kramer’s own investigation where he went to watch trials taking place. He then realised for himself that the patients were volunteers struggling financially and were motivated to pretend they had depression in order to participate thereby receiving their fee. “So, Peter concluded that the results from clinical trials of anti-depressants – all the data that we have – are meaningless”. In other words, Kirsch was correct with his assessment.
More recently in 2018, Andreas Cipriana published in the Lancet medical journal what was considered to be the largest piece of research into SSRIs. He conducted 522 trials with 116,477 participants comparing 21 of the most commonly prescribed anti-depressants. The findings of Cipriana’s research seemed to swing the pendulum back in favour of the chemical imbalance theory. He concluded that “all antidepressants were more efficacious than the placebo in adults with major depressive disorders”. (Newman, 2019). However, Cipriano’s research was not without its criticism and a disconnect was further created between those that support the administering of SSRIs as a treatment for depression and those that don’t. Dr Klaus Monkton questioned “Dr Cipriana didn’t address certain biases in the data – were participants adequately blinded?” (Newman, 2019). There were also questions into Cipriano’s length of study where participants only had 8 weeks of treatment.
Another major critic of the serotonin theory is Professor Joanna Moncrieff who Hari interviews in his book, the Lost Connections (2019). Moncrieff is very dismissive of the theory on the basis that we don’t really know what a ‘chemically balanced’ brain looks like. She disputes the proposal that anti-depressants “restore a natural balance to your brain”. (Hari 2019, p36). Instead they “create an artificial state” and “the whole idea of mental distress being caused simply by a chemical imbalance is ‘a myth’ sold to us by the drug companies.”
Bringing this debate into current times, the biological theory around chemical imbalance is pretty much debunked. Moncrieff & Horowitz (2022) state that “the serotonin theory of depression has been one of the most influential and extensively researched biological theories of the origins of depression”. However, very few people now believe in this theory due to the inadequacies of the scientific evidence. Kirsch (2014) commented that “the serotonin theory is as close as any theory in the history of science to have been proven wrong”.
Nevertheless, SSRIs are still used as a way of treating depression and its ‘bed-fellow’ anxiety. The reason for this is that they do seem to work for some people, but we do not yet fully understand why. It is thought that they act by numbing emotions and taking the edge off depression but this is not proven as an absolute. Moncrieff & Horowitz (2022) comment that “other possible reasons for SSRIs are that they appear to have an emotion-numbing effect, but there is still a lack of evidence”. Some members of the medical community believe that SSRIs should no longer be prescribed because we don’t fully understand how they work, there are still real side-affects and we can’t say what the long-term impact of taking these medications is. Instead, the pharmaceutical companies should be looking into other medications that are empirically proven to work and better understood. There seems to be an impasse, but it is unlikely that SSRIs will disappear anytime soon. This is because there isn’t an alternative, the medication is low cost and the pharma industry continues to reap high levels of profit.
So, if the biological theory is no longer considered accurate, let’s consider current thinking. For this we need to take a wider more bio-psycho-social model. This means that to understand depression, you need to look at three overlapping causes: biological, psychological and social. “All three sets of factors are relevant, and to understand a person’s depression, you need to look at them all”. (Hari 2019, p66). It is generally considered that there are biological aspects to depressive disorders. A person whose genetic family has a history of depression are more prone to experiencing depressive symptoms during their life; however, this does not mean that they will develop such a disorder. There are other psychosocial factors that need to come into play. Examples of these are a physical or psychological traumatic event, early attachment issues, significant grief, poverty, gender and other illnesses (e.g. stroke, cancer). These psychosocial factors can also bring about depression for people who do not have a history of the condition in their family.
In summary, depression remains a complex disorder and can have many subcategories (e.g. bipolar and borderline personality disorder both involve depression). It can be mild or chronic. Cooper & Dryden (2016, p233-234) say that “there is evidence the ‘depression’ is not a single entity and often occurs in combination with other issues such as anxiety, trauma and substance misuse and long-term health problems”. Although we understand it better than in previous decades, there is still much to learn. A combination of both psychotherapy and pharmacology seems to be the most effective treatment, but there is no guarantee that this will work and some people have a life-long battle with depression that they may try to manage through different addictions that are equally self-defeating (e.g. narcotics, alcohol). The good news is that depression is losing its social stigma through greater media publicity and an openness by people who are suffering from the disorder to discuss it (e.g. Michael Phelps, Katy Perry, Bruce Springsteen, Lady Gaga, Dwayne Johnson). You are no longer alone and this in itself has some healing properties.
References
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