The counterbalance between leptin and cortisol may be associated with comorbid depression and anxiety

Abstract

Details of the psychopathologic relationship that exists between major depression and leptin are uncertain. However, the comorbidity which is known to occur between major depression and anxiety disorders may help elucidate this controversy. In addition to their comments on the heterogeneity of obsessive-compulsive disorder (OCD), Atmaca and colleagues have also provided important insight regarding the heterogeneity of major depression. 1 In theory, hyperactivity of the hypothalamo–pituitary–adrenal (HPA) axis, yielding an elevated level of cortisol, is an important pathogenic factor for major depression. From a dynamic perspective, previous neuroendocrinological studies have established that the HPA axis responds quickly to acute stress. The HPA axis also has the capacity to adapt to chronic stress so that further responsiveness is maintained. 2 Leptin, a neuropeptide derived primarily from peripheral adipose tissue, may provide negative feedback inhibition to the HPA axis which is crucial for adapting to chronic stress. 2 Psychopathology would be the result if such a mechanism of counterbalance was impaired. Hence, compromised suppression of cortisol secretion by a reduced level of leptin could precipitate major depression. It is thus feasible that the role of leptin to a hyperfunctioning HPA axis, as occurs in major depression, may be influenced by a psychiatric comorbidity. Many community-based epidemiological studies have shown that major depression is often accompanied by anxiety disorders. Hypoleptinemic subjects with both major depression and OCD may in fact have an impaired feedback loop involving the HPA axis, which in turn may contribute to hyperactivity of the HPA axis. In a study involving the victims of a giant earthquake, hyperleptinemia was demonstrated in the subjects exhibiting persistent partial posttraumatic stress disorder (PTSD), yet during an 18-month followup did not meet the diagnostic criteria of major depression. 3 Hypothetically, hyperleptinemia may correlate with excessive inhibition of the HPA axis, manifesting as a lower cortisol level in PTSD. The activity of the HPA axis differs between PTSD and major depression. 4 However, dysfunction of the counterbalance between leptin and cortisol in the opposing direction, irrespective of the cause (i.e. PTSD or major depression with comorbid OCD), is plausible. Future research which investigates the relationship between major depression and leptin should consider psychiatric comorbidities. Such a possibility has not been addressed by previous studies. Structured diagnostic algorithms may be required to identify an anxiety syndrome. Those with pure major depressive episodes and with comorbid anxiety disorders may have a different etiology in the pattern or impact of the leptin–cortisol interaction.