Anxiety was defined in 1844 by the Danish philosopher Søren Kierkegaard and is often referred to as ‘the dizziness of freedom’. Imagination is central in defining anxiety, as Søren Kierkegaard emphasized, when differentiating between fear and anxiety. Imagination and thoughts are central in the processes in which we perceive the world and our possibilities, and these processes have an enormous impact on the brain, body, and life of human beings. His paradigmatic viewpoints thus placed cognitive cerebral functions as a causal mechanism in anxiety and depression.
Today, anxiety and depression are often considered two sides of a coin and consequently treated similarly with serotonin reuptake inhibitors. The present serotonin hypothesis supporting the use of this drug suggests that serotonin, an important neurotransmitter in the mammalian brain, increases in the synaptic junctions primarily in the anterior cingulate cortex and that blocking the synaptic reuptake helps to alleviate anxiety, reduce negative mood, and increase motivation. Nevertheless, despite modern treatment, depression remains a major disease entity and is expected to be the second most common global disease by 2020 1. Moreover, the serotonin hypothesis per se remains largely undocumented and the clinical evidence for selective serotonin reuptake inhibitor (SSRI) treatment effect also challenges the concept 2,3.
In this paper, we suggest a redefinition for the serotonin hypothesis. The new hypothesis includes anxiety and depression as evolutionary meaningful behavioral responses in mammalian biology. In the frontal cortex, such reaction patterns can be elicited by both external stimuli and cognition-mediated perspectivation based on imagination. In the depression reaction, which is phenotypically characterized by lack of motivation and energy, the organism saves energy while waiting for changes in the external environment or in the imaginary feared situation. As all situations change over time, the energy-saving behavior (abandonment reaction) renders the organism ready for pursuing new possibilities when they appear. From a behavioral point of view, changes in the fearful environment often occur from the abandonment reaction, as is seen in, for instance, animals caught in a situation with no obvious possibility of escape.
A second argument in the redefinition suggests that anxiety and depression are not well explained by the serotonin hypothesis; instead, they are entities caused by the cognitive mind. In this argument, the frontal cortex responds both to cognitive processes and to physiological stimuli from the organism. Thus, the feeling of, for instance, ‘a galloping heart’ during periods of anxiety, or for that matter during atrial fibrillation, will be processed in the frontal lobes (cognition) as being potentially dangerous and lead to changes in end behavior. If so, it will affect the limbic system to elicit further flight reactions. Abdominal sensations (often mediated by the vagal nerve) may also be critically involved in a negative cognitive spiral when perspectivating the individual’s possibilities in the world with a negative focus. The cognitive mind evaluates such bodily feelings as potentially negative (dangerous), and they further enhance the negative loop thinking, which can ultimately lead to an abandonment reaction, namely, depression. Cognition thus gathers both physical and imaginary stimuli to place the organism in the context of the surroundings and decides the final behavior from these inputs and perspectives. The end result, that is, depression, often leads to a marked reduction in energy expenditure, as the possibility for reward (sexual, food, social contact) is evaluated as not possible. The depressive reduction in energy expenditure, however, may be beneficially saved for better times to come, which again places depression as not merely meaningless in an evolutionary context. The perspective made by the frontal lobes is therefore crucial to the following processes in the human limbic system.
Treatment with modern serotonin reuptake inhibitors may offer alleviation to some depressed patients. However, the clinical data are not uniform and the ‘proof of concept’ of increased serotonin in the brain can certainly be disputed. Serotonin was first identified as a potent vasoactive substance in circulation mostly stored in platelets 4. The immediate serotonin release in the circulatory system caused by increased adrenaline is associated with prompt vasoconstriction and increased heart function, and is thus a part of priming the organism for rapid mobilization and action. In relation to the abdominal reaction in depression, the opposite phenomenon will happen – that is, reduced vasoconstriction and heart function. We hypothesize that the drug effects may also relate to physical changes in hemodynamics with a decrease in cardiac pulse and blood pressure amplitude occurring after 6–8 weeks of treatment 5. The depressed cardiovascular system, in turn, will be perceived as a sensation of release and the negative cognition will decrease. If this holds true, new clinical testing of antidepressive drugs should then be compared with other known depressors of cardiovascular function, such as standard β-blockade or angiotensin-converting enzyme inhibition. Finally, the serotonin pool in the platelets should be evaluated together with their aggregation abilities, as it is well known that treatment with SSRI is associated with a better outcome in depressed patients with cardiovascular comorbidity 6,7.
For now, our redefinition of the serotonin hypothesis places anxiety and depression as potentially meaningful behavior and states that the epicenter for sustaining this behavior is defined by cognition and not cerebral serotonin. Future research on treating anxiety and depression should therefore address cognition as the primary target for therapy and medical options including SSRI as adjuvant therapy in alleviating unpleasant physical symptoms. Also, the systemic serotonin homeostasis deserves renewed attention, as SSRI treatment will also affect the serotonin reuptake transporter in organs outside the brain. In perspective, serotonin reuptake inhibition may even hold a place in treating cardiovascular disease in the absence of anxiety and depression.
Conflicts of interest
There are no conflicts of interest.
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