The Antidepressant Controversy

The widespread use of Selective Serotonin Reuptake Inhibitors (SSRIs) as the first-line treatment for depression is clearly not justified by the research; clinical effectiveness is questionable and potentially do not out-weigh the side effects.


Selective serotonin reuptake inhibitors (SSRIs) are the antidepressants recommended as the first-line treatment for the majority of patients with major depressive disorder (MDD) in the UK and internationally (Bauer et al., 2007) (Cleare et al., 2015). The primary mechanism by which SSRIs are believed to treat depression is by increasing serotonin availability in the brain (Harmer et al., 2017; 410). However the serotonin (5-HT) hypothesis of depression does not adequately account for the delayed onset and questionable efficacy of SSRIs (Ellis and Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression, 2004) (Bauer et al., 2007) (Kennedy et al., 2016) (Liu et al., 2017). ‘The rapid increase of 5-HT concentration in the synaptic cleft of neurons is inconsistent with the clinical delayed onset of antidepressant efficacy’ (Liu et al., 2017).

How are antidepressants supposed to work?

Down-regulation of 5-HT1A Receptors

Consistent SSRI treatment has been shown to desensitize and down-regulate 5-HT1A auto-receptors in animals and humans (Marsteller et al., 2007) (Siesser et al., 2013). One theory attempting to explain the delay in onset of therapeutic action is that this is the time needed for auto-receptor desensitization and down-regulation (Romero et al., 1996). If this theory is correct it would follow that combining SSRIs with 5-HT1A selective auto-receptor antagonists should significantly increase the onset of therapeutic anti-depressant effect. However this method has yet to be shown clinically effective (Stahl, 2013).

Stress, Depression and the Hypothalamic-Pituitary-Adrenocortical (HPA) axis

The relationship between stress and depression is well documented (Biegler, 2008) (Binder and Nemeroff, 2010) (Pizzagalli, 2014). Hypothalamic-Pituitary-Adrenocortical (HPA) axis over-activation, elevated cortisol levels and hippocampal volume reduction are commonly seen in depressed patients (Varghese and Brown, 2001) (Holsen et al., 2013). It is believed that HPA axis regulation may be an additional action mechanism of SSRIs although studies using cortisol levels as a measure have been inconclusive and somewhat contradictory.

Neuroplasticity Theory

The neuroplasticity hypothesis of MDD may provide a more credible theory for depression and antidepressant efficacy (Liu et al., 2017). Neuroplasticity is the ability of a neural system to adaptively respond to internal and external stimuli, as well as future stimuli (Cramer et al., 2011). Decreased concentration of neurotrophic factors as well as decreased neuroplasticity has been documented in depressed patients. It is suggested that antidepressants increase the concentration of neurotrophic factors subsequently improving neuroplasticity in the brain (Serafini, 2012) (Harmer et al., 2017).

Increasing neurogenesis in the hippocampus via activation of postsynaptic monoamine G-protein coupled receptors may be an explanation of how SSRIs treat depression via the neuroplasticity hypothesis (Liu et al., 2017). SSRIs may also regulate neuroplasticity by stabilizing glutamate neurotransmission in the hippocampus (Bonanno et al., 2005). Reduction of glutamate release could strengthen synaptic connections and neurogenesis (Sanacora et al., 2012). Research for this hypothesis is again in its early stages.

Do antidepressants actually work?

The answer to the inconsistencies discussed above may be that the actual efficacy of SSRIs is questionable. A recent systematic review of SSRIs looked at 131 trials with 27,422 patients suffering from MDD and found minor statistical improvements but questionable clinically significant improvements as well as a high risk of bias in the majority of trials (Jakobsen et al., 2017).

Another large systematic review looked at the overall efficacy of all antidepressant drugs in 522 trials with over 100,000 patients found modest clinically significant improvements for antidepressants (Cipriani et al., 2018). However they also found that 82% of trials had at least a moderate risk of bias and that the certainty of evidence was ‘moderate to very low’. The study also declared significant conflicts of interests with links to multiple pharmaceutical companies and associations.

Studies by (Kirsch, 2000) (Kirsch, 2014) found that 80-90% of the effectiveness of anti-depressant medication is due to the setting, protocols and ritual of the consultation with a primary care physician, whereas only 10-20% of the effectiveness is attributed to a specific bio-chemical (vs placebo) mechanism.

Furthermore SSRIs have been shown to decrease in efficacy with long-term use (Byrne and Rothschild, 1998) (Fava et al., 1995). Whether SSRIs are clinically effective in the treatment of Major Depressive Disorder is highly questionable. Furthermore there is little evidence for a relationship between stable blood concentration levels of SSRIs and clinical effects (Hiemke and Härtter, 2000; 17, 22) (Danish University Antidepressant Group, 1990) (Kush and Hegerl, 1998) (Leonard, 1992). These inconsistencies in SSRI efficacy and action mechanism should absolutely call into question whether we should be recommending these drugs as the first line of treatment for depression.

St John’s wort vs antidepressants (SSRI’s)

St John’s wort (guan ye lian qiao) has been used in Traditional Chinese herbal medicine for thousands of years to treat depression. The most recent Cochrane review for the efficacy of St John’s wort for depression looked at 29 trials with 5,489 patients and found St John’s wort superior to placebo, similar in effectiveness to anti-depressants and with lower risks of side effects (Linde et al., 2008). These conclusions were confirmed by a more recent systematic review which looked at 27 clinical trials with 3,808 patients (Ng et al., 2017). Systematic reviews and meta analysis have confirmed significantly lower rates of side effects for St John’s wort compared to SSRIs as well as significantly lower discontinuation rates in trials (Ng et al., 2017) (Apaydin et al., 2016).

However St. John’s wort (Hypericum perforatum) has been shown to affect the pharmacokinetics of several drugs by inducing CYP isozymes including; CYP3A4, CYP2C19, CYP2C9 as well as the transporter Pgp making it a potentially problematic herb for a variety of drugs which are metabolised via these same pathways (Ang-Lee et al., 2001) (Izzo and Ernst, 2001). The evidence is still not fully clear, but is conclusive enough to recommend that St John’s wort is potentially dangerous and should be contra-indicated for patients who are also taking SSRIs (Greeson et al., 2001) (Fugh-Berman, 2000) (Zhou et al., 2004a) (Henderson et al., 2002).

Given the similarity in clinical effectiveness between St John’s wort and SSRIs, patients suffering from MDD would be best advised to chose either one or the other and avoid co-administration. St John’s wort may be more advantageous due to its lower risk of adverse effects. The research on efficacy is strong enough that primary care physicians should recommend this as an alternative option to patients.

Side effects of antidepressants

SSRIs are generally considered to less toxic compared to other tricyclic antidepressants (de Jonghe and Swinkels, 1992). However an analysis of the literature clearly shows there are some very problematic side effects associated with SSRI use.


Discontinuation can be an indicator of adverse effects and poor efficacy. Fluvoxamine generally shows the highest discontinuation rates due to side effects in clinical trials (<70% within 2 months). Fluoxetine (45%) and sertraline (40%) also show high rates of discontinuation (Goldstein and Goodnick, 1998). SSRI discontinuation syndrome may occur when a patient stops taking an SSRI abruptly after a long-term use and includes flu-like symptoms including; nausea, diarrhea, fever, paraesthesia, dizziness, headache and insomnia (Haddad, 1998).

Common Adverse Effects

Gastrointestinal side effects such as nausea are common, occurring in 15–35% of patients taking SSRIs (Rickels and Schweizer, 1990). Vomiting and/or diarrhea have been reported, as have an increase in severity of tension headaches and migraines during SSRI treatment (Sampson, 2001). Other side effects include tremors, anxiety and outbursts of anger in a small percentage of users (Walsh and Dinan, 2001). Reports of mania vary, some reporting it in 10–20% of patients (Goldberg, 2000) but more commonly mania is reported in under 5% (Peet, 1994).

Significant weight gain (7% increase) in long-term SSRI use is estimated as 25.5% for Paroxetine, 6.8% for Fluoxetine and 4.2% for Sertraline (Fava, 2000). There is a complicated multi-factorial link between obesity and depression, it has been suggested that each may increase risk of developing the other (Lee et al., 2016).

Sexual dysfunction (lack of libido, erectile dysfunction, anorgasmia, painful orgasm) is experienced in 30–40% of patients taking SSRIs (Rothschild, 2000). A study including 344 patients listed a higher frequency of adverse sexual side effects in different SSRIs; Paroxetine (65%), Fluvoxamine (59%), Sertraline (56%) and Fluoxetine (54%) (Montejo-González et al., 1997). It is highly probable that both weight gain and sexual dysfunction as a side effect of taking SSRIs in already depressed patients could risk exacerbate their depression.


Side effects of SSRIs have been found to be far more frequently occurring than what was originally reported in the early clinical trials, especially in regards to sexual dysfunction (Rosen et al., 1999). A recent systematic review found that 3.1% of SSRI users with MDD will experience a serious adverse event compared with 2.2% of control participants (Jakobsen et al., 2017). SSRIs were shown to significantly increase non-serious adverse effects in depressed patients. Most alarmingly the review found that there was almost no data included in any of the trials studying ‘suicidal behavior, quality of life and long-term effects’.

The extent of SSRI efficacy is questionable and the working mechanism is unclear. A variety of adverse side effects are common and the data on increased risk of suicide is scarce and understudied. Significantly lower adverse effects and discontinuation rates have been demonstrated for St John’s wort compared to SSRI’s with comparable efficacy, especially for mild to moderate depression, suggesting this may be safer alternative for a lot of patients (Ng et al., 2017) (Apaydin et al., 2016). As Jakobsen et al (2017) conclude: SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.’

Nick Lowe MSc

February 2019


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