The noradrenergic paradox: implications in the management of depression and anxiety

Abstract

Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these studies was anxiety a treatment-emergent adverse effect. This review argues against the impression that enhanced generalized noradrenergic activity promotes the emergence of anxiety.

Keywords: anxiety; atomoxetine; desvenlafaxine; duloxetine; monoamine; norepinephrine reuptake inhibitor; norepinephrine transporter.

Figure 1

Illustration of presynaptic and postsynaptic noradrenergic receptors. Notes: NE is released from noradrenergic nerve terminals, where it diffuses across the synaptic cleft and activates adrenergic receptors to elicit a postsynaptic effect. In addition, inhibitory α₂-adrenergic autoreceptors residing on the presynaptic terminal regulate the further release of NE from the terminal. The action of NE at the synapse is terminated in part by the reuptake of NE into the presynaptic terminal, where it can undergo catabolism by MAO and COMT. Abbreviations: COMT, catechol-O-methyltransferase; DHPG, dihydroxyphenylglycol; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; NE, norepinephrine.

Figure 2

NETs and synaptic function in noradrenergic transmission. Notes: NE released into the synaptic cleft is transported back into the presynaptic nerve terminal by NET. NE may be degraded intracellularly or extracellularly by the catabolic enzymes MAO and COMT. Abbreviations: AADC, aromatic L-amino acid decarboxylase; AMPT, alpha-methyl-p-tyrosine; COMT, catechol-O-methyltransferase; DA, dopamine; DA β-H, dopamine-β-hydroxylase; DOPA, 3,4-dihydroxyphenylalanine; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; NE, norepinephrine; NETs, norepinephrine transporters; NM, normetanephrine; TH, tyrosine hydroxylase.

Figure 3

Search strategy. Notes: Flow chart showing the progression of the search strategy employed in this investigation. Literature searches were performed with PubMed, EMBASE, and the Cochrane Library. The searches were filtered to exclude those that did not include randomization, placebo, and controls. Finally, the search results were combined (n=263). Duplicate results were eliminated to reveal a final value of 206 studies. *Represents a wildcard character, to capture various words starting with anxi, eg, anxiety, anxious, etc.

Figure 4

Monoaminergic systems and potential interactions. Notes: The potential for interactions among noradrenergic, serotonergic, and dopaminergic neurons is illustrated. Receptor activation by each of these monoaminergic transmitters may be excitatory or inhibitory, depending on the receptor subtype that is activated. Abbreviations: DA, dopamine; 5-HT, 5-hydroxytryptamine; NE, norepinephrine.

Figure 5

Tonic and phasic noradrenergic activity. Notes: Tonic background noradrenergic activity represents the normal awake, alert resting state. Excessively low noradrenergic activity is associated with drowsiness and cognitive impairment. External stimuli, such as a threat, results in a momentary increase in noradrenergic firing rates, representing a phasic response, which is associated with enhanced vigilance and reflexes. A maladaptive increase in phasic response rates is associated with anxiety or panic attacks and cognitive impairment. Noradrenergic reuptake inhibitors can elevate depressed tonic noradrenergic function into the normal, basal range. However, enhanced tonic firing of noradrenergic neurons can dampen excessive phasic firing through the activation of inhibitory autoreceptors. Abbreviations: MAOI, monoamine oxidase inhibitor; NE, norepinephrine; NRI, norepinephrine reuptake inhibitor; REM, rapid eye movement sleep; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.