Prediction of Clinical Response to Antidepressants in Patients with Depression: Neurophysiology in Clinical Practice

INTRODUCTION

In patients with depression several drug trials with different antidepressants are often needed within a “trial and error approach,” before a sufficient clinical treatment response can be achieved. Nevertheless, at least 30–50% of patients with major depression do not respond to the first or second medication administered. ^1,2 The definite determination whether individual patients are nonresponders to specific antidepressants requires a period of at least 2 to 3 weeks, owing to the well known latency of clinical antidepressive effects. ² Furthermore, in case of nonresponse repeated drug trials may follow. This procedure is time consuming, might lead to increasing distress to the patients and even increase the risk of self-harm, suicidality, and chronicity.

The development of a neurobiological parameter for a reliable prediction of the individual patients' responses to different antidepressive drugs would allow immediate, adequate and effective drug treatment, and shorten the disease process, thus preventing chronicity or sustained therapy-resistance. In addition, indirect and direct cost of treatment could significantly be reduced. To date, based on the current knowledge of the pathophysiology of depression, ³ highly selective antidepressive agents are available, acting differentially, e.g., via the serotonergic or noradrenergic system.

However, what is urgently needed, are predictors of treatment response, which allow for a preselection of the best drug strategy for the individual patient. This kind of prediction should possibly be based on information regarding the respective functions of central serotonergic or noradrenergic pathways. Thus, one promising way to predict response to antidepressants could be based on the identification of neurochemical subtypes of depressed patients. The use of selective serotonin reuptake inhibitors (SSRI), with their long-term enhancement of serotonergic metabolism, should be effective for a favorable outcome, especially in depressive patients with low central serotonergic activity, whereas the use of noradrenaline reuptake inhibitors (NARI) should be indicated in patients with normal serotonergic but presumably low noradrenergic function. ⁴

INDICATORS OF CENTRAL MONOAMINERGIC ACTIVITY

The reliable identification of such pathophysiological differences, however, is difficult, since direct or specific indicators for serotonergic or noradrenergic pathways are still lacking, and peripheral biochemical indicators only indirectly and therefore insufficiently reflect central noradrenergic or serotonergic neurotransmission. ^5,6 However, in recent years, several preclinical and clinical studies showed that the loudness dependence of auditory evoked potentials (LD) is a valid indicator of the central serotonergic activity. ^{7 –10} The reactivity of the auditory cortex can be assessed using the N1/P2-component of the auditory evoked potentials. This potential occurs about 70–200 ms after presentation of acoustic stimuli and shows pronounced interindividual differences regarding its loudness dependence. The N1/P2-component can reliably be detected and its generating structures have largely been identified. There is converging evidence from intracranial recordings and from lesion studies that the N1/P2-component is composed of overlapping subcomponents generated by primary as well as secondary auditory cortices. In animal experiments serotonergic transmission within the primary auditory cortex is much more pronounced than in the secondary auditory cortex. ^11,12 Juckel et al. ¹³ were able to demonstrate in cats that enhancing or blocking serotonergic activity in the dorsal raphe nucleus led to a decrease or increase in LD only in the primary but not in the secondary auditory cortex.

The differentiation of the electric brain activity within these regions can be estimated in humans by means of a dipole source model with two dipoles representing the primary (tangential dipole) and the secondary (radial dipole) auditory cortex, respectively. ¹⁴ The LD can be measured as the slope of the amplitude/loudness function: the LD of the N1/P2 component of the primary auditory cortex is high, when the activity of the serotonergic system is low, and vice versa. A detailed description of the method is given elsewhere. ¹⁵

In the clinical setting LD has been successfully used as a noninvasive indicator of the central serotonergic system, e.g., in ecstasy users (suspected damage of the central serotonergic system) or patients with borderline personality disorder, ^16,17 to predict patients' response to selective serotonin reuptake inhibitors, ^18,19 to establish central effects of antimigraine drugs (i.e., triptans) ²⁰ or for detection and monitoring of central serotonin syndromes. ²¹ The observation that allelic variants of the serotonin transporter gene differ with respect to the LD further supports the hypothesis of an association between the serotonergic system and neurophysiological measures, as well as the correlation of LD with serotonin transporter availability as assessed by nuclear medicine imaging techniques such as SPECT with the monoamine transporter ligand β-CIT ^{22 –24} In accordance with animal data, differences in the LD between different groups of subjects (patients vs. controls, responders vs. nonresponders) were consistently more pronounced in analyses of brain structures representing the primary auditory cortex, e.g., by using the tangential dipole in a two-dipole model of dipole source analysis, or other techniques such as LORETA, or fMRI. ^{9,16,19,25 –27}

Some conflicting results should also be reported: electrophysiological studies using serotonergic challenge tests with tryptophan depletion or acute citalopram infusions have not consistently shown modulation of the LD in humans. ^{28 –31} Nevertheless, Kahkonen et al. ³² showed an influence of acute tryptophan depletion on the intensity dependence of auditory magnetic N1/P2 dipole source activity and Nathan et al. ³³ demonstrated in healthy subjects that the enhancement of serotonin function by oral citalopram decreased the LD compared with placebo, again supporting the notion that serotonin participates in the regulation of LD. Methodological limitations might be responsible for the negative results, and it has to be taken into account that LD might not entirely be specific for central serotonergic activity, and that dopaminergic properties may also play a role in modulating cortical auditory stimulus processing. ^22,24,34,35

PREDICTION OF TREATMENT RESPONSE

CONCLUSION

The presented data point to a potential use and applicability of LD assessments in clinical practice as a differential predictor of the first therapeutic response to a treatment with either serotonergic or noradrenergic antidepressants. As a consequence, patients could benefit from advanced recovery without experiencing side effects of an otherwise ineffective pharmacotherapy.

It must be made clear, however, that the above data are preliminary and larger confirmatory trials are needed. LD as a response predictor will by no means replace clinical judgment as the most important aspect of good clinical management. But by providing additional information, this auxiliary method may offer valuable assistance for clinicians in treatment decisions. Furthermore, the LD as a noninvasive technique can easily be performed, is a quick and safe neurophysiological procedure and could thus be introduced into daily clinical routine of in- or out-patient services and clinical practices.