According to the World Health Organization, about 121 million people across the globe suffer from depression and the WHO has ranked depression as fourth in a list of most urgent problems worldwide (2). It is the most prevalent psychiatric disorder and is responsible for nearly 850,000 deaths every year. Supporting this fact, statistics have revealed that the use of anti-depressants has soared over 400 percent in the past two decades (3). According to Kresser, a licensed acupuncturist and practitioner of integrative medicine, several chemically distinct anti-depressants – marketed under trade names such as Prozac, Zoloft, and Paxil – now enjoy immense popularity as anti-depressants (4). Amongst the four classes of anti-depressant medication, namely selective serotonin reuptake inhibitors (SSRIs), atypical depressants, tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors (MAOIs), SSRIs have been the most widely prescribed medication by physicians. In this essay, the terms SSRI and anti-depressant will be used interchangeably.
The current model of SSRIs assumes that a low level of extracellular neurotransmitter, serotonin, is primarily responsible for depression. Serotonin in our body can be found in two places – 80 percent of it in our gastrointestinal tract while the rest in our brain (5). The 80 percent of serotonin function as hormones and they play a role in muscular contractions whereas the 20 percent act as a neurotransmitter in our brain (6). In our brain there are many cells called neurons, which are separated by small “gaps”. Messages carried by neurotransmitters are delivered from one neuron to another across the gaps. These messages come in the form of chemical impulses, and contain information about mood, behaviour, body temperature, appetite and sleep. Once a neurotransmitter leaves the sending neuron, it will “latch” onto the receiving neuron and relay chemical impulses over. Then the neurotransmitter returns to its sending neuron to be re-used again – this process is called reuptake. On the other hand, if there are inadequate amounts of neurotransmitters, the next impulse does not fire off and messages will not be relayed. (7) SSRIs work to block or slow down the reuptake of serotonin in particular, hence increasing the amount of extracellular serotonin. As a result, more serotonin are present in the gaps which will increase rate of successful transmission of impulses to the receiving neuron. SSRI is hence engineered on the belief that serotonin is the cause of depression. However ever since the advent of the drug and its side-effects exposed, drug researchers are compelled to re-investigate the efficacy of SSRIs, in which confounding results were revealed.
The investigation into the serotonin-depression link will not only prevent doctors making inappropriate prescriptions that may not be in the best interest of their patients’ health, it also allows a clearer definition of the causes of depression. Ultimately, establishing the proper function of serotonin may lead to a ground-breaking change in the methodology of treating depression and related disorders in the psychiatric and pharmacology world.
While most people concur with the belief that a deficiency of serotonin is related to depression, some argue that an imbalance in serotonin levels leads to depression. This imbalance theory arises because of the widespread notion that SSRIs are only effective for patients with moderate to severe depression while it is ineffective for mildly depressed patients. The basis of the debate surrounding the efficacy of SSRIs in fact boils down to a deeper problem – whether or not the neurotransmitter, serotonin, is related to depression at all. Nevertheless, I oppose both claims of the serotonin-depression link and contest that there is no coherence between levels of serotonin and depression. Up till now, there have no substantial evidence that depression is caused by serotonin deficiency, neither is there one that shows that over stimulation of serotonin causes depression.
Efficacy of SSRIs challenged by small drug-placebo difference
Many studies have shown that the efficacy of SSRI drugs in the treatment of depression is challenged by low drug-placebo difference scores. Studies to investigate the efficacy of anti-depressants by giving placebos to a controlled group have revealed that the recovery rate of patients who took a glucose pill was equivalent to patients who consumed the anti-depression drug (8). A 2008 meta analysis of the efficacy of SSRIs that was published by the Food and Drug Administration (FDA), revealed that these anti-depressants have no clinically significant edge over all placebos. By this, it means that it did not meet the drug licensing authority, UK National Institute of Clinical Excellence (NICE) standards. As evident in the meta analysis, the placebo response groups account for up to 75 percent of all positive effects of anti-depressant medication (9) which shows that 3 in 4 of all patients who reported an increase in heightened emotional well-being were actually consuming sugar pills. Other studies yielded similar results – a study by Khan et al. found a 10 percent difference in level of symptoms when patients consume the inert placebos compared to the active drugs in two separate meta-analyses (10). As the drug-placebo difference is small, it can be seen that regardless of whether SSRI is administered or not, symptoms of depression are still greatly reduced. This implies that serotonin level may not be related to depression at all.
Opponents argue that experiments to test the efficacy of SSRIs against inert placebos may not be accurate because the side effects of SSRIs are not mimicked. They claim that commonly known side effects of SSRIs, such as diarrhoea, nausea, dizziness, headaches or even gastrointestinal bleeding (11) may affect patients’ mood, which in turn underrate the impact of serotonin in lifting depression. This claim is however rejected by many scientific literatures which show counter-evidences. According to Joanna Moncrieff, the co-chair person of Critical Psychiatry Network, when she used active placebos to simulate the adverse-effects of SSRIs in anti-depressant drug trials, results revealed that differences between active placebo and SSRI were significantly small (12). To measure severity of depression before and after the drug trials, the conventional Hamilton Rating Scale of Depression (HRSD) was used. Since it did not meet NICE standards of an improvement in rating score of 3 points to be defined as clinically significant (8), the above studies involving inert and active placebos clearly show that no matter which placebo type was administered – active or inert, drug versus placebo significance in anti-depressant efficacy is “clinically insignificant”. Whether or not the level of serotonin is increased, patients reported a reduction in symptoms of depression, therefore there is little evidence to say that a lack of this neurotransmitter causes depression.
Another common belief by proponents of anti-depressants is that initial severity of depression is directly related to the effectiveness of SSRIs, that SSRIs work best for patients with very severe depression. It is thought that over stimulation of serotonin may cause further chemical imbalance in patients suffering from mild depression, hence rendering SSRIs ineffective (13). Thus in order to test this claim, Kirsch et al moved on to investigate whether initial severity of depression affects the efficacy of anti-depressants. He tested on the hypothesis that anti-depressants work only for people suffering from moderate to major depression. In this double-blinded study of 35 clinical trials involving 5,133 subjects, both drug administers and subjects were unknown to results of randomized medication (placebo or SSRI) to prevent sampling biasness and subjects’ severity of depression was measured by HRSD (14). The test was conducted to see if there is an improvement in the subjects’ depression, measured against their baseline severity and the final conclusion is as follows: patients with an initial moderate depression did not report a drug-placebo difference, patients with an initial severe depression reported a relatively small drug-placebo difference and only for patients situated at the upper end of very severe depression category did the drug-placebo difference fall into the clinically significant criterion by NICE standards (8). Although effectiveness of SSRIs may seem to improve with the severity of depression, further research has revealed a negative coherence between severity and placebo response. As highlighted from Figure 1, the drug-placebo difference reached clinical standards for people with a higher initial severity of depression. Further analysis shows that a higher drug-placebo difference is due to a decrease in improvement of the placebo group rather than due to the effects of SSRIs.
Figure 1. Mean Standardized Improvement as a Function of Initial Severity and Treatment Group, Including Only Trials Whose Samples Had High Initial Severity
This implies that the increased benefit for extremely depressed patients seems attributable to a response-deficiency to placebos rather than a heightened response to SSRI medication. Therefore efficacy of SSRI does not increase with severity of depression and increasing amount of serotonin did not work for patients with all levels of depression. Since SSRIs are designed to alleviate depression by inhibiting the reuptake of serotonin in our brain cells, it shows that there is no relationship between extracellular serotonin and one’s mood. Furthermore, it usually take weeks before effects of anti-depressants are expressed and can be measured by testing for serotonin levels in the blood, yet patients often report relief within hours or days of medication. Therefore this phenomenon demonstrates the lack of correlation between serotonin and depression and gives support to the placebo effect.
The lack in correlation is further evidenced by the results of a Force Swim Test (FST). FST, also known as the behavioural despair test, is a conventional anti-depressant screening test which involves using rodents as test subjects. In this test, rats are dropped in an enclosed water cylinder and their movements observed. The “struggling” time of rats is measured based on the assumption that immobility of rats is directly proportional to their state of depression. For example depressed rats will cease trying and float in the cylinder, which is akin to despair, whereas non-depressed rats will continue to struggle in search of a way out (15). Although it is thought that SSRIs should extend struggling time of rats, final results were inconsistent hence inconclusive (16). The administration of SSRIs in rodents did not make them less susceptible to depression, displaying no direct relationship between serotonin and depression. Nonetheless, it should be noted that experiments done on mice may not be entirely accurate in predicting responses in humans (17).
The bold assumption made by researchers
The serotonin-depression link came about when scientists first discovered that in most depressed patients, the level of serotonin is comparably lower than that in non-depressed people. The amount of serotonin in a human’s body was measured by comparing blood samples taken from depressed and healthy people. Subsequently the anti-depressant SSRI was invented, which targets the neurotransmitter serotonin and works to stimulate the production of it. This methodology then raises a few doubts. Firstly, the assumption that blood serotonin and brain serotonin are directly proportional can be contested as it is certainly impossible to measure the amount of serotonin in the brain. Patients who have high levels of serotonin in the blood may have low levels of serotonin in the brain and vice versa. As mentioned earlier, 80 percent of the human’s body total serotonin is found in our bloodstream and the rest in the brain. While the level of blood serotonin can be measured, current biomedical technology has yet to transcend the brain barrier. In all clinical trials involving SSRIs, the assumption made is that blood serotonin reflects brain serotonin, which is a very bold one to make. This then creates a paradox in research methodology: the reason for inventing SSRIs instead of feeding serotonin directly to a human’s body is due to the “blood-brain barrier”. Orally ingested serotonin are ineffective as they do not pass through bloodstreams into the brain, that is – the digestive system is unparallel to the central nervous system. Whereas SSRIs work because they merely seek to enhance an impulse that is already present, but too feeble to cross the ‘gap’. Yet scientists conveniently established a link between serotonin and depression by measuring serotonin in patients’ blood. It is reasonable to say that since blood serotonin is not proven to be a clear indication of brain serotonin, any positive outcomes of anti-depressant drug trials may not be due to the increase in brain serotonin but other unknown factors. This again shows a lack of tangible evidence between the neurotransmitter, serotonin, and depression.
Secondly, in all probability that there is a direct attestation of serotonin deficiency in any mental disorder lacking, it is still unclear whether low levels of serotonin causes depression or depression causes a dip in serotonin. Evidences supporting the latter can be based on observations of non-depressed people with low amounts of serotonin. In a 1996 investigation of the biochemistry of depression, attempts made to induce depression by reducing serotonin levels yielded no consistent results (18). Similarly, researchers found that a surge in brain serotonin, arrived at by administering SSRIs, were ineffective at alleviating depression (19). Therefore there is little evidence to support serotonin as a mood chemical.
Also problematic for the serotonin-depression claim is the expanding field of research comparing SSRIs to other anti-depression drugs that do not target serotonin specifically (20). For instance, the atypical anti-depressant buproprion (21) and St. John’s Wort (22), which do not alter the level of serotonin were proven to be just as effective as SSRIs in the treatment for depression. Therefore doubts about the serotonin-depression link are acknowledged by many researchers as well as by advocates of SSRIs (23). To supplement my stand, serotonin is not listed as the cause of depression disorder in the Diagnostic and Statistical Manual of Mental Disorders (24). The American Psychiatric Press Textbook of Clinical Psychiatry (25) also reiterates that serotonin deficiency as an unconfirmed hypothesis (20). In short, there exists no rigorous corroboration of the serotonin theory, which may suggest the reliability of positive drug trials published by drug companies.
In addition to what textbooks have to say about serotonin, it is important to look at what not being said in scientific literature. There are numerous peer-reviewed articles supporting the disconnect between serotonin and depression however not a single one can be precisely cited to directly endorse claims of a serotonin deficiency in any mental disorders (20). Assuming that blood serotonin is a good measure for brain serotonin, abundant evidences of high placebo significance in anti-depressant drug trials, the rejection of the claim that efficacy of SSRIs depends on severity of depression, and an inconsistent Force Swim Test results indicate that serotonin may not be the cause of depression. No doubt there may be a positive outcomes from the drug trials, however because blood serotonin may not reflect brain serotonin, these outcomes coupled with the above mentioned proofs against the serotonin hypothesis strongly suggest that other factors are involved in depression. The incongruence between the scientific literature and the claims made by proponents are prominent, hence I stand for the fact that there is no direct correlation between serotonin level and depression.