Depression is a complex multifactorial neuropsychiatric condition which is associated with a high burden of disease [1-3]. Depression disturbs mood and cognition resulting in poor functioning and a significant detriment to the quality of life [1, 3-5]. It is one of the most prevalent disorders affecting more than 300 million individuals globally [6]. Five per cent of the Australian population suffer from depression each year [7]. Depression is characterised by a high recurrence rate; 40% of the treated patients relapse within 12 months [1]. Moreover, 20% to 30% of patients receiving a treatment for depression, achieve partial remission [1]. These patients continue to experience partial negative symptoms and suffer from daily life limitations. Depressive disorders are heterogenous and include a wide variety of biological and psychopathological endophenotypes [8]. Psychopathological endophenotypes include depressed mood, anhedonia, impaired learning and memory, appetite change, diurnal variation and stress [9]. Biological endophenotypes include REM sleep abnormalities, catecholamine depletion, downregulation of serotonin (5-HT) receptors, tryptophan (L-Trp) depletion and high cortisol levels [9]. The current diagnosis of depressive disorders and monitoring treatment success involve the use of depression assessment scales [9]. These scales are based on subjective markers; patients’ symptoms. Hence, the current diagnosis and treatment of depression can be affected by clinicians’ bias to a higher extent in the absence of accurate biomarkers guiding the diagnosis and treatment of depression.
To date, there are no acknowledged objective markers employed to monitor treatment response of antidepressants in practice. The delayed response of antidepressants and the lack of accurate markers guiding the treatment therapy hinders physicians’ clinical decisions during the initial weeks of treatment. Having objective biological markers to study depressive symptoms can improve the initial treatment of depression by modelling patients’ disease state and their responses to antidepressant interventions.
Initially, depression was linked to a relative deficiency of monoamine neurotransmitters in the synaptic cleft such as 5-HT and noradrenaline (NA) [3, 5]. This is known as the monoamine theory of depression [3, 14]. 5-HT levels were used as a marker to guide the efficacy of treatment for depression. Soon after, researchers discovered the limitations of the monoamine hypothesis. Although, antidepressants medications correct the levels of neurotransmitters at the synapse within a few hours after the first dose, a period of four to six weeks is needed to achieve the full antidepressant effects in improving patients’ mood as outlined in Figure 1 [15]. Additionally, the current antidepressants medications have a success rate of approximately 60% [15]. This highlights a limitation in this theory and suggests the involvement of alternative mechanisms to ameliorate mood other than the direct effect of antidepressants on the level of neurotransmitters at the synapse.
Figure 1 – Overview of mechanisms involved in depression and antidepressants mechanism of actions
Many studies identified relevant biological markers that are associated with depression. Recent evidence suggests a correlation between depression and neuroinflammation causing a disruption to L-tryptophan (Trp) and kynurenine pathway (KP) along with the neopterin to biopterin (N/B) ratio [10-12]. Several studies focused on the Trp depletion and upregulation of the KP in certain endophenotypes of depression whereas limited studies have investigated the potential of using neopterin to biopterin (N/B) ratio as a marker to monitor antidepressants’ treatment response. Evidence suggests that a rise in N/B ratio in depressed patients correlates with the severity depressive symptoms [12].
Overall, depression remains on of the most prevalent conditions with a high disease burden. Current depression treatments have a 60% success rate require four to six weeks to show their full effect. Understanding the different mechanisms that may be involved in the pathophysiology of depression, will assist identifying novel, more effective treatments and relevant biomarkers that can monitor treatment response.
Mina Malek, BBiomedSc, MPharm (Senior Scientific Advisor at My Medical Department)
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