By Anna Miteniece
When asked about major depressive disorder (MDD), colloquially referred to simply as depression, professor Robert Sapolsky described it as ‘the clinical inability to enjoy sunsets.’ (Sapolsky, 2020) An apt portrayal of the serious physiopsychological affliction characterized by pervasive low mood, anhedonia, low self-esteem and pain without a clear cause. Unsurprisingly, these symptoms lead to a great decrease in quality of life of affected individuals and in some cases compel them to commit suicide. (Depression, 2020)
Unfortunately, depression is not a fringe disorder found only in astronauts that experience 16 sunrises and sunsets each day. In 2017 World Health Organization (WHO) reported that MDD affected 242 million people worldwide (a whooping 3% of the world’s population) and many studies show that this number is increasing each year, particularly among adolescents aged 12-17. (WHO, 2017) In addition, age-adjusted suicide rates in the USA have increased by an estimated 30% from 2000 to 2016 and similar trends can be observed in other developed countries. (Major Depression: The Impact on Overall Health, 2020) Thus, depression and the treatments of it are of great interest to contemporary psychiatrists, politicians, pharmacological companies and general public alike, especially since the Covid-19 pandemic has wrecked chaos on the already unstable socioeconomic conditions and challenged people’s ability to cope with the increasingly depressing reality of surviving in today’s world.
Great progress has been made in treating depression. Older methodology involved demon exorcisms and dream therapy with Freudian scholars, while today a depressed individual is advised to attend psychotherapy sessions or/and use antidepressants. Underlying these shifts are changes in the public and scientific consensus on the causes of the illness, with contemporary models emphasizing the biochemical imbalances in the brain as the root of the issue, while previous models centered around the environmental influences on the individual. (Horwitz, Wakefield and Lorenzo-Luaces, 2016) Consequently, the most common medical treatment of MDD currently is the administration of a group of antidepressants called selective serotonin reuptake inhibitors (SSRIs). (Kravitz et al., 2005) A method predicated on the assumption that the diminished presence of the neurotransmitter serotonin in various neural pathways is responsible for the symptoms of depression in affected individuals. (Cowen, 2008) We will see that this assumption is highly contested by various studies and that the success of SSRIs in clinical trials is not as clear-cut as the prevalence of SSRI prescriptions may indicate.
Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter synthesized from the amino acid tryptophan in the terminal axon of serotonergic neurons, which are important in mediating autonomic brain function, motor activity and complex cognitive processes involving emotional processing and reward/punishment systems. (Cowen and Browning, 2015) The serotonin hypothesis of depression has been around for approximately 50 years and is based on the statistically reliable observation that depressed patients have lower plasma levels of tryptophan than healthy controls. Their blood platelets also show diminished uptake of the compound. (Cowen, 2008) This implicates decreased serotonin levels in the synaptic cleft in the pathophysiology of depression but does not reveal much else about the mechanism by which MDD arises. In addition, abnormal 5HT pathway function doesn’t seem to be unique to patients with depression and is present in people with other psychiatric disorders (e. g. generalized anxiety disorder and schizophrenia). (Lacasse and Leo, 2005)
Interestingly, when blood tryptophan levels are depleted by manipulating dietary intake of the amino acid, studies show that healthy controls do not experience any significant decrease in mood, or display any other MDD symptoms, whereas patients who had recovered from depression displayed a rapid, but demonstrable relapse. (Sharp and Cowen, 2011) Thus, it’s likely abnormalities in 5HT pathways are involved in compromising maintenance of recovery in depressed patients rather than inducing an acute depressive state in all vulnerable people. The data strongly suggests that these abnormalities are neurobiological ‘scars’ left by previous depressive episodes, instead of being the cause behind them. (Shyn and Hamilton, 2010) Thus, it could be extrapolated that treatments like SSRIs and monoamine oxidase inhibitors (MAOs) that work to increase serotonin levels might be more useful to patients undergoing recovery than acutely affected individuals.
More proof for the serotonin hypothesis comes from observations of psychiatrists that administering SSRIs help patients with MDD, albeit after a lag period of 2-3 weeks. (Kravitz et al., 2005) SSRIs inhibit the SCL6A4 serotonin transporter in the presynaptic cleft that transports 5HT back into the presynaptic terminals. (Sangkuhl, Klein and Altman, 2009) However, this widespread consensus about the efficacy of SSRIs is surprisingly highly contested by clinical data.
A comprehensive metanalysis by I. Kirsch et al. in 2002 looked at the clinical trial data of 6 brands of SSRIs submitted to and approved for general use by the US FDA. All trials were funded by pharmacological companies. 47 six-week double blind trials with various sample sizes were done on moderately to severely depressed outpatients and inpatients that looked at the changes in their Hamilton Depression Scale (HAM-D) scores (from 0-29, higher score indicating more severe symptoms) when given either placebo or an SSRI treatment. Mean improvement scores were not reported in 9 of the 47 trials. Only data of three of the antidepressants were consistent and complete over the course of the 6-week trial period, yielding 19 trials to be analyzed with a total sample size of 3708 people. (Kirsch et al., 2002)
Interestingly, both SSRI and placebo groups showed a statistically significant improvement during the trials, with SSRI treated patients showing a 10-point decrease in HAM-D scores on average and an 8-point decrease in the placebo group. The weighted mean difference between the drug and placebo groups across these three medications was only 1.80 points on the HAM-D (a small, but statistically significant difference t18 = 5.01, p < .001) and only about 18% of the drug response may be attributed to the pharmacological effect of the medication itself. (Kirsch, Scoboria and Moore, 2002) Furthermore, it is estimated that 50% of the trials funded by the pharmaceutical industry found no significant difference in HAM-D scores pre and post treatment and were never published, thus the drug response estimate would come down to about 10% instead, if all results were considered. (Thase, 2002) Similar studies done with patients suffering from mild to moderate symptoms (lower HAM-D) of MDD revealed no statistical difference between placebo and SSRI groups. (Kirsch, Scoboria and Moore, 2002)
However, a different metanalysis of the same dataset revealed that in groups treated with SSRIs, prevalence of side effects was significantly higher than in placebo groups. These included impaired sexual function, akathisia, and alarmingly – suicidal ideation. (Thase, 2002) All previously mentioned trials involved adults (aged 19+) and most studies of suicidality after SSRI treatment in adults reveal no significant increase. However, when similar studies are done on children and adolescents (6-18) SSRI treatment is significantly associated with increased suicide attempts and deaths. (Kupfer, Frank and Phillips, 2012)
Given the tentative link between serotonin and depression and the clinically dubious efficacy of SSRIs, the finding that in 30% of cases a doctor will prescribe these medications to patients describing symptoms of MDD may seem surprising. This estimate rises to 53%, if the patient mentions a specific brand of antidepressant. (Kravitz et al., 2005) Direct-to-costumer advertisement campaigns for various SSRIs are ubiquitous and the market for these drugs is concerningly bloated. (Lacasse and Leo, 2005) The contemporary obsession with medicalizing sadness stems from a need for an individualistic quick fix that can be marketed as a consumable product, rather than investing in the sustainable long-term wellbeing of society. Childhood trauma and excessive stress are the most powerful predictors of depression later in life. These issues are better, more efficiently addressed by continued psychotherapy and physical exercise on an individual level and by reduction of social insecurity and implementation of robust support networks. (Kupfer, Frank and Phillips, 2012) SSRIs can be useful for some individuals suffering from depression, albeit statistically this number is surprisingly small, but they do not address the root causes of the illness and thus fail profoundly in treating it on a societal scale.
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