Differential Prediction of First Clinical Response to Serotonergic and Noradrenergic Antidepressants Using the Loudness Dependence of Auditory Evoked Potentials in Patients With Major Depressive Disorder

Juckel, Georg; Pogarell, Oliver; Augustin, Holger; Mulert, Christoph; Müller-Siecheneder, F.; Frodl, Thomas; Mavrogiorgou, Paraskevi; Hegerl, Ulrich

doi:10.4088/jcp.v68n0806

Cited by 101 publications

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“…If we assume that the LDAEP predominantly reflects central serotonergic function, then the range of the LDAEP in the placebo condition suggests that this naturally varies considerably. Taking this further, it suggests the SSRI treatment 1 Several studies have reported that a stronger baseline LDAEP in MDD patients predicts a more favourable response to SSRI treatment than patients with a weaker LDAEP (Gallinat et al 2000;Juckel et al 2007;Mulert et al 2007). employed here augmented 5-HT levels, but only into the upper levels of the normal range.…”

Section: Discussionmentioning

confidence: 96%

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

et al. 2011

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We show for the first time that chronically modulating serotonin neurotransmission alters the LDAEP in healthy adults, consistent with extant literature indicating a moderating role of serotonin on this neurophysiological biomarker. The findings from this study together with previous studies suggest that the LDAEP may be a more sensitive marker of long-term or chronic rather than acute changes in the serotonin system.

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Section: Discussionmentioning

confidence: 96%

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

et al. 2011

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“…A weak LDAEP has been observed after pharmacological treatment with serotoninagonistic drugs such as zimelidine, sertraline, and lithium (Buchsbaum and Pfefferbaum, 1971;Hubbard et al, 1980;Von Knorring, 1982) or, in contrast, a strong LDAEP in schizophrenic patients after long-term use of serotoninantagonistic substances (5-HT2A receptor) such as clozapine and olanzapine . Furthermore, patients with a low serotonergic activity show a favorable response to serotonergic medication (Gallinat et al, 2000;Juckel et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Loudness Dependence of Auditory Evoked Potentials as Indicator of Central Serotonergic Neurotransmission: Simultaneous Electrophysiological Recordings and In Vivo Microdialysis in the Rat Primary Auditory Cortex

Wutzler

Winter

Kitzrow

et al. 2008

Neuropsychopharmacol

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Serotonin released in synapsis is one of the key neurotransmitters in psychiatry and psychopharmacology. The loudness dependence of auditory evoked potentials (LDAEP) has been proposed as a marker for central serotonergic neurotransmission. Several findings in animals and humans support this hypothesis. However, the in vivo measurement of cortical extracellular serotonin levels has never been performed simultaneously with the recording of auditory evoked potentials. The interrelationship between low cortical serotonergic activity and strong LDAEP is yet to be proven. The auditory evoked potentials were recorded in the epidura above the primary auditory cortex of male Wistar rats whereas extracellular serotonin levels in the primary auditory cortex were measured by in vivo microdialysis before and after i.p. application of the selective serotonin reuptake inhibitor citalopram. At baseline, the correlation of coefficients between the LDAEP, especially of the N1 component, and extracellular serotonin levels in the primary auditory cortex was negative. The increase of serotonin levels after citalopram application was significantly related to a decrease of LDAEP of the N1 component (r ¼ À0.86, p ¼ 0.003). These data support the view that the LDAEP is closely modulated by cortical serotonergic activity. Thus, the LDAEP might serve as an inversely related marker of synaptically released serotonin in the CNS.

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“…57 The LDAEP's ability to predict antidepressant response has been replicated by more groups than for any other EEG method described above, and includes more patients than any other technique. 37,[58][59][60][61][62][63][64][65] Critically, the LDAEP is also reported to be able to predict response to serotonergic and noradrenergic antidepressants differentially. 57,66 In the light of these findings, an obvious question is whether or not the ability to predict antidepressant response is improved by combining different EEG parameters.…”

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Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

et al. 2015

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BackgroundDepressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. TheAntiglucocorticoid augmentation of antiDepressants inDepression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.ObjectiveTo determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.MethodsA total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.ResultsThe estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.DiscussionThe inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.ConclusionsThe results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.Trial registrationCurrent Controlled Trials ISRCTN45338259.Funding detailsThis study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

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Differential Prediction of First Clinical Response to Serotonergic and Noradrenergic Antidepressants Using the Loudness Dependence of Auditory Evoked Potentials in Patients With Major Depressive Disorder

Cited by 101 publications

References 0 publications

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

Loudness Dependence of Auditory Evoked Potentials as Indicator of Central Serotonergic Neurotransmission: Simultaneous Electrophysiological Recordings and In Vivo Microdialysis in the Rat Primary Auditory Cortex

Randomised controlled trial of Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD Study)

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