Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder

Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious nonaddictive pharmacotherapies for ADHD.

Disturbed relationship between glucocorticoid receptor and 5-HT1AR/5-HT2AR in ADHD rats: A correlation study

“…A collection of evidence has revealed that ADHD is associated with monoamine neurotransmitters, like serotonin (5-HT), dopamine (DA), and noradrenaline (NE) ( Mogavero et al, 2018 ). 5-HT system plays a vital role in ADHD from genetics, biochemistry, nerve pathology, and psychological perspectives ( Riley and Overton, 2019 ). Furthermore, the prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level of cognitive and emotional processes, which are commonly disrupted in mental illnesses, such as ADHD ( Hiser and Koenigs, 2018 ; Yan and Rein, 2022 ).…”

Serotonergic and Adrenergic Neuroreceptor Manipulation Ameliorates Core Symptoms of ADHD through Modulating Dopaminergic Receptors in Spontaneously Hypertensive Rats

“…It has been well established that reduced levels of NE and DA in the brain are associated with ADHD. Of late, it has also been shown that a reduced 5-HT level in the prefrontal cortex is a characteristic of ADHD-like impulsive and hyperactive behavior which could be reversed with selective 5-HT reuptake inhibitors [39]. Though it is understood that 5-HT plays a major modulatory role in prefrontal cortex function, it is not clear which 5-HT receptors exert these effects.…”

“…Chronic treatment with 5-HT1A receptor agonists (for example, buspirone) has been known to cause antidepressant and anxiolytic effects in both animal and human studies. In contrast to this, Riley and Overton [39] suggest utilizing 5-HT1A antagonists as a potential way forward in the development of pharmacotherapies for ADHD.…”

Transient depersonalisation/derealisation syndrome from tramadol

“…Although the role of these neurotransmitters in the pathogenesis of DD is not well established, evidence suggests that treatment with norepinephrine agonists can either exacerbate or improve DD symptoms 11 16 17. Moreover, the patient’s underlying ADHD, which involves complex interactions among dopamine, norepinephrine and serotonin,18 may increase susceptibility to unexpected serotonergic effects of tramadol. However, further investigation is needed to substantiate these speculations.…”