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  • Writer's pictureEmma

The First-Line Combo: SSRI and CBT

Updated: Sep 28, 2023

Pharmacological interventions for psychiatric and neurological conditions often target neurotransmitters including dopamine, norepinephrine, and serotonin. Nevertheless, first-line therapies for depression have overwhelmingly focused on serotonin (1,3).

The role of serotonin in human mood and behaviour first emerged in the 1960s, when the antihypertensive drug reserpine was found to induce depression in hypertensive patients while also depleting neurologic monoamines, including serotonin: This discovery prompted the idea that augmenting serotonin levels in the brain might provide antidepressant effects. Image from Freepik

The first Selective Serotonin Reuptake Inhibitor (SSRI) was introduced two decades later and marked a turning point in the treatment of depression (2). To understand further the mechanisms underlying SSRIs we can dive further into the physiology of serotonin itself.

The majority of serotonin is intracellular, therefore its concentration can be tightly regulated through the release into the synaptic cleft and through a negative feedback mechanism. When an action potential occurs, presynaptic vesicles release serotonin into the cleft, triggering post-synaptic neuron stimulation. Activation of G-protein coupled receptors sets off both excitatory and inhibitory second messenger cascades within the post-synaptic neuron. SSRIs act at the presynaptic membrane blocking negative feedback receptors that normal halt further serotonin release. The Image by Freepik activity of serotonin in the cleft is therefore extended, enhancing post-synaptic stimulation (3).

The positive findings of SSRIs supported the monoamine hypothesis of depression, which states that a deficiency in serotonin, norepinephrine and dopamine is the biological cause of depression. For this reason, first-line treatments also include Serotonin Norepinephrine Reuptake Inhibitors (SNRIs). When both SSRIs and SNRIs fail, Monoamine Oxidase Inhibitors (MAOIs) are prescribed (2). It is meaningful to note that the monoamine hypothesis is only a partial explanation for the development of depression. We do not why serotonin stores are lower in depressed patients or why certain SSRIs works for some patients and not for others. This lack of knowledge is possibly why pharmacological treatment cannot stand as the gold standard treatment alone (4).

The combination of pharmacotherapy with cognitive behavioural therapy (CBT) has demonstrated enhanced efficacy and reduced relapse rates. Pharmacotherapy with CBT is recommended for mild, moderate, and chronic depression. Guidelines do support more sessions and extended follow up for more severe cases. CBT is based on the cognitive model of depression. The cognitive model postulates that the view people have of life events is more influential than the event itself. A negative view can lead to automatic thoughts of helplessness, hopelessness, and worthlessness. CBT aims to the rewire this dysfunctional cognitive reaction. Fortunately, there are no concrete contraindications to CBT. Additional training may be required for treating patients with severe depression with psychosis and/or patients with comorbid personality disorders. While CBT is recommended to all patients, certain factors can predict the success rate of therapy. Those who can express and label their emotions tend to respond best. Motivation and willingness to receive treatment also tend to show a better response (4).

Learning to treat depression has taken a lot of progress over decades. While serotonin has played a central role in pharmacological interventions, it’s important to recognize that the monoamine hypothesis is only one piece of the puzzle. Often different SSRIs are prescribed until the patient finds what works for them since depression is such a individualized disorder. CBT with pharmacotherapy has become the standard of care, providing a holistic approach addressing the cognitive and emotional responses to stressful events. More and more alternatives are on the horizon as well as research in this field grows, which promises more effective and personalized care for individuals facing these challenges, because as we know depression is often a lifelong struggle that may only be managed and not cured in many cases.

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  1. Popovic, D., Vieta, E., Fornaro, M., & Perugi, G. (2015). Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRI antidepressants. Journal of Affective Disorders. 173, 211-215.

  2. Owens, M. J. (2004). Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. Journal of Clinical Psychiatry. 65(4), 5-10.

  3. Bamalan, O. A., Moore, M. J., & Al Khalili, Y. (2023). Physiology, Serotonin. StatPearls, [Internet]. Available from:

  4. Gautam, M., Tripathi, A., Deshmukh, D., & Gaur, M. (2020). Cognitive Behavioral Therapy for Depression. Indian Journal of Psychiatry. 62(2), 223-229.

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