Selective serotonin re-uptake inhibitors (SSRIs) are a second-generation anti-depressant and first-line treatment for Generalised Anxiety Disorder (GAD) (Stuivenga et al., 2019;Cvjetkovic-Bosnjack et al., 2015). Although it is not fully understood why SSRIs are effective for GAD symptoms, it is hypothesised GAD has similar neurochemical dysfunction as unipolar disorders therefore SSRIs assist GAD symptoms (Nutt et al., 2002; Judd et al., 1998). SSRIs act on serotonergic receptor sites (Holck et al., 2019).
Serotonergic neurons are found in the corticolimbic system, including the amygdala, hippocampus and prefrontal areas of the brain (Andolina et al., 2015). Dysfunctional serotonergic receptor functioning is observed in GAD at 5-HT1 and 5-HT2 receptor sites in the limbic system (Bocchio et al., 2016; Pytliak et al., 2011). Additionally, mice bred without the G-protein coupled 5-HT1A post receptor site in the limbic system, show anxious behaviours, supporting the role of serotonin in GAD, (Hjorth et al., 2000; Sánchez & Meier, 1997).
In corticolimbic areas of the central nervous system, SSRIs act as blocking agents preventing 5-HT transporter proteins from regulating the neurotransmitter into serotonergic autoreceptors of the pre-synaptic neuron (Harmer et al., 2017). This leads to extracellular abundance of 5-HT at the synapse, increasing neurotransmission at post-synaptic receptor sites and preventing pre-synaptic regulation of 5-HT (Hjorth, 2016). Specifically, SSRIs binding to sites such as the G-protein coupled 5-HT1 receptor predominantly found in the hippocampus (Pazos et al., 1984). A subtype of which is the somatodendritic 5-HT1A autorecepter primarily located in the raphe nuclei (Raid et al., 2000). Other presynaptic 5-HT receptors are found in the hippocampus, amygdala and prefrontal areas of the brain (Meneses, 1999). Although there are five members of the 5-HT1receptor, 5‐HT1A and 5‐HT1B have been researched most for pharmacotherapy treatments of anxiety (Raid et al., 2000). SSRIs displace the research chemical 8-OH-DPAT from 5-HT1A sites suggesting SSRI usage for GAD (Pazos et al., 1984). Additionally, research shows dysfunction at 5-HT binding sites is associated with anxiousness and aggression, symptoms of GAD (Pytliak et al., 2011).
Sertraline (SSRI) is significantly effective in GAD symptom treatment (Brawman-Mintzer et al., 2006). However, Holck (2019) recently found individuals with lower 5-HT levels in blood plasma prior treatment did not respond to sertraline.
Paroxetine (SSRI) has been extensively studied in GAD treatment with double-blind trials showing paroxetine improves work and social engagement (Nutt et al., 2002). However, paroxetine shows discontinuation-related symptoms similar to benzodiazepine withdrawal syndrome and may not be a first choice SSRI (Dominguez & Goodnick, 1995).
Use of SSRIs can lead to excessive intra-synaptic 5-HT levels which can cause serotonin toxicity. Benzodiazepines can be considered as alternatives should toxicity occur, as they interact with other neurochemical mechanisms (Gillman, 2005). A common side-effect of SSRI usage is sexual dysfunction (Clayton et al., 2002). While it is not fully understood why this occurs, it is hypothesised that receptor sites 5-HT1A and 5-HT1B experience excessive corticolimbic 5-HT levels which consequently relates to decreased sexual desire (Pytliak et al., 2011). There is some evidence to suggest SSRIs paradoxically cause suicide (Teicher et al., 1990). However, other research suggests there is no greater suicide prevalence in SSRI users than a placebo control group (Kahn et al., 2003). Perhaps more research is needed for clarification.
Calarge et al. (2017) argue body composition needs critical consideration when considering SSRI treatment. They found SSRI dosage and treatment-length varied for different sex, BMI, fat-mass and muscle-mass scores. Therefore, consideration should be taken for GAD treatment, as patients are initially prescribed the same SSRI by well-meaning physicians (Davis et al., 2013). Additionally, Ekhart et al. (2018) found women are more likely to have adverse reactions from SSRIs than men. And confirmed by Holck (2019) finding those with lower levels of 5-HT in plasma did not respond to SSRIs.
Cvjetkovic-Bosnjack et al. (2015) suggest patients undergo Cognitive Behavioural Therapy alongside SSRI treatment.
Offidani et al. (2013) conclude from their meta-analysis that evidence for why SSRIs are the first line of treatment for GAD is inconclusive. Interestingly, benzodiazepines have fewer side effects and fewer discontinuations. However, benzodiazepines are highly addictive and GAD symptoms have been known to increase in severity after discontinuation (Chouinard, 2004).